Certain chemical entities, compositions, and methods

ABSTRACT

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.

This application is a continuation-in-part of application Ser. No.11/121,709, filed May 3, 2005 and Ser. No. 11/124,608, filed May 6,2005, and claims the benefit of U.S. Patent Application No. 60/569,510,filed May 6, 2004. Each of those applications is hereby incorporated byreference.

Provided are certain chemical entities which are inhibitors of one ormore mitotic kinesins and are useful in the treatment of cellularproliferative diseases, for example cancer, hyperplasias, restenosis,cardiac hypertrophy, immune disorders, fungal disorders, andinflammation.

Among the therapeutic agents used to treat cancer are the taxanes andvinca alkaloids, which act on microtubules. Microtubules are the primarystructural element of the mitotic spindle. The mitotic spindle isresponsible for distribution of replicate copies of the genome to eachof the two daughter cells that result from cell division. It is presumedthat disruption of the mitotic spindle by these drugs results ininhibition of cancer cell division, and induction of cancer cell death.However, microtubules form other types of cellular structures, includingtracks for intracellular transport in nerve processes. Because theseagents do not specifically target mitotic spindles, they have sideeffects that limit their usefulness.

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms. Examples of this include notonly the taxanes, but also the camptothecin class of topoisomerase Iinhibitors. From both of these perspectives, mitotic kinesins areattractive targets for new anti-cancer agents.

Mitotic kinesins are enzymes essential for assembly and function of themitotic spindle, but are not generally part of other microtubulestructures, such as in nerve processes. Mitotic kinesins play essentialroles during all phases of mitosis. These enzymes are “molecular motors”that transform energy released by hydrolysis of ATP into mechanicalforce which drives the directional movement of cellular cargoes alongmicrotubules. The catalytic domain sufficient for this task is a compactstructure of approximately 340 amino acids. During mitosis, kinesinsorganize microtubules into the bipolar structure that is the mitoticspindle. Kinesins mediate movement of chromosomes along spindlemicrotubules, as well as structural changes in the mitotic spindleassociated with specific phases of mitosis. Experimental perturbation ofmitotic kinesin function causes malformation or dysfunction of themitotic spindle, frequently resulting in cell cycle arrest and celldeath.

Provided is at least one chemical entity chosen from compounds ofFormula I

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R₁ is chosen from optionally substituted aryl, optionally    substituted heterocycloalkyl, and optionally substituted heteroaryl;-   X is chosen from —CO and —SO₂—;-   R₂ is chosen from hydrogen and optionally substituted lower alkyl;-   W is chosen from —CR₄—, —CH₂CR₄—, and N;-   R₃ is chosen from —CO—R₇, hydrogen, optionally substituted alkyl,    optionally substituted heterocycloalkyl, optionally substituted    heteroaryl, cyano, sulfonyl, and optionally substituted aryl;-   R₄ is chosen from hydrogen and optionally substituted alkyl;-   R₅ is chosen from hydrogen, hydroxy, optionally substituted amino,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl;optionally substituted heteroaryl, and optionally    substituted lower alkyl;-   R₆ is chosen from hydrogen, optionally substituted alkyl, optionally    substituted alkoxy, optionally substituted aryloxy, optionally    substituted heteraryloxy, optionally substituted alkoxycarbonyl-,    aminocarbonyl-, optionally substituted aryl, optionally substituted    heteroaryl, optionally substituted cycloalkyl, and optionally    substituted heterocycloalkyl; and-   R₇ is chosen from optionally substituted lower alkyl, optionally    substituted aryl, hydroxy, optionally substituted amino, optionally    substituted aralkoxy, and optionally substituted alkoxy;-   provided that if W is N, then R₅ is not hydroxy or optionally    substituted amino, and R₆ is not optionally substituted alkoxy,    optionally substituted aralkoxy, optionally substituted    heteroaralkoxy, or optionally substituted amino.

Also provided is a composition comprising a pharmaceutical excipient andat least one chemical entity described herein.

Also provided is a method of modulating CENP-E kinesin activity whichcomprises contacting said kinesin with an effective amount of at leastone chemical entity described herein.

Also provided is a method of inhibiting CENP-E which comprisescontacting said kinesin with an effective amount of at least onechemical entity described herein.

Also provided is a method for the treatment of a cellular proliferativedisease comprising administering to a subject in need thereof at leastone chemical entity described herein.

Also provided is a method for the treatment of a cellular proliferativedisease comprising administering to a subject in need thereof acomposition comprising a pharmaceutical excipient and at least onechemical entity described herein.

Also provided is the use, in the manufacture of a medicament fortreating cellular proliferative disease, of at least one chemical entityof described herein.

Also provided is the use of at least one chemical entity describedherein for the manufacture of a medicament for treating a disorderassociated with CENP-E kinesin activity.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence.

The following abbreviations and terms have the indicated meaningsthroughout:

-   -   Ac=acetyl    -   Boc=t-butyloxy carbonyl    -   Bu=butyl    -   c-=cyclo    -   CBZ=carbobenzoxy=benzyloxycarbonyl    -   DCM=dichloromethane=methylene chloride=CH₂Cl₂    -   DCE=dichloroethane    -   DEAD=diethyl azodicarboxylate    -   DIC=diisopropylcarbodiimide    -   DIEA=N,N-diisopropylethylamine    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   Et=ethyl    -   Fmoc=9-fluorenylmethoxycarbonyl    -   GC=gas chromatography    -   HATU=O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HOAc=acetic acid    -   HOBt=hydroxybenzotriazole    -   LAH=lithium aluminum hydride    -   Me=methyl    -   mesyl=methanesulfonyl    -   NCS=N-chlorosuccinimide    -   Ph=phenyl    -   Py=pyridine    -   rt=room temperature    -   sat'd=saturated    -   s-=secondary    -   t-=tertiary    -   TES=triethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TMS=trimethylsilyl    -   tosyl=p-toluenesulfonyl

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or “the” kinase is inclusive of one or more kinases.

Formula I includes all subformulae thereof. For example Formula Iincludes compounds of Formula II.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆ alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric combinations having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having one to fourcarbons.

“Alkenyl” refers to an unsaturated branched or straight-chain alkylgroup having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the cis or trans configuration aboutthe double bond(S). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like. In certainembodiments, an alkenyl group has from 2 to 20 carbon atoms and in otherembodiments, from 2 to 6 carbon atoms.

“Alkynyl” refers to an unsaturated branched or straight-chain alkylgroup having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certainembodiments, an alkynyl group has from 2 to 20 carbon atoms and in otherembodiments, from 3 to 6 carbon atoms.

“Cycloalkyl” indicates a non-aromatic carbocyclic ring, usually havingfrom 3 to 7 ring carbon atoms. The ring may be saturated or have one ormore carbon-carbon double bonds. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, andcyclohexenyl, as well as bridged and caged saturated ring groups such asnorbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy,2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy groupswill usually have from 1 to 7 carbon atoms attached through the oxygenbridge. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

“Mono- and di-alkylcarboxamide” encompasses a group of the formula—(C═O)NR_(a)R_(b) where R_(a) and R_(b) are independently chosen fromhydrogen and alkyl groups of the indicated number of carbon atoms,provided that R_(a) and R_(b) are not both hydrogen.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant a group of the formula (alkoxy)(C═O)—attached through the carbonyl carbon wherein the alkoxy group has theindicated number of carbon atoms. Thus a C₁-C₆ alkoxycarbonyl group isan alkoxy group having from 1 to 6 carbon atoms attached through itsoxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkylamino groups, wherein the alkyl groups are as defined above and have theindicated number of carbon atoms. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

The term “aminocarbonyl” refers to the group —CONR^(b)R^(c), where

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 5- to 7-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms selected from O, N, and S in the heterocycloalkylring;

-   where each substituted group is independently substituted with one    or more substituents independently selected from C₁-C₄ alkyl, aryl,    heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄    haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH,    —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄    alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄    alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (as a    substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl),    —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),    —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl),    —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl),    —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl,    —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄    haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),    —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

“Aryl” encompasses:

-   -   6-membered carbocyclic aromatic rings, for example, benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.        For example, aryl includes 6-membered carbocyclic aromatic rings        fused to a 5- to 7-membered heterocycloalkyl ring containing 1        or more heteroatoms chosen from N, O, and S. For such fused,        bicyclic ring systems wherein only one of the rings is a        carbocyclic aromatic ring, the point of attachment may be at the        carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent        radicals formed from substituted benzene derivatives and having        the free valences at ring atoms are named as substituted        phenylene radicals. Bivalent radicals derived from univalent        polycyclic hydrocarbon radicals whose names end in “-yl” by        removal of one hydrogen atom from the carbon atom with the free        valence are named by adding “-idene” to the name of the        corresponding univalent radical, e.g., a naphthyl group with two        points of attachment is termed naphthylidene. Aryl, however,        does not encompass or overlap in any way with heteroaryl,        separately defined below. Hence, if one or more carbocyclic        aromatic rings is fused with a heterocycloalkyl aromatic ring,        the resulting ring system is heteroaryl, not aryl, as defined        herein.

The term “aryloxy” refers to the group —O-aryl.

“Carbamimidoyl” refers to the group —C(═NH)—NH₂.

“Substituted carbamimidoyl” refers to the group —C(═NR^(e))—NR^(f)R^(g)where R^(e), is chosen from: hydrogen, cyano, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocycloalkyl; and R^(f) and R^(g) are independently chosen from:hydrogen optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocycloalkyl, provided thatat least one of R^(e), R^(f), and R^(g) is not hydrogen and whereinsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroarylrefer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from:

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R_(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or R_(b) and R^(c), and the nitrogen to which they areattached, form an optionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂ NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Haloalkyl” indicates alkyl as defined above having the specified numberof carbon atoms, substituted with 1 or more halogen atoms, up to themaximum allowable number of halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or in certain embodiments, from        1 to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon;    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or in certain embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring; and    -   tricyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 5, or in certain embodiments, from 1 to 4,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.        For example, heteroaryl includes a 5- to 7-membered        heterocycloalkyl, aromatic ring fused to a 5- to 7-membered        cycloalkyl or heterocycloalkyl ring. For such fused, bicyclic        heteroaryl ring systems wherein only one of the rings contains        one or more heteroatoms, the point of attachment may be at        either ring. When the total number of S and O atoms in the        heteroaryl group exceeds 1, those heteroatoms are not adjacent        to one another. In certain embodiments, the total number of S        and O atoms in the heteroaryl group is not more than 2. In        certain embodiments, the total number of S and O atoms in the        aromatic heterocycle is not more than 1. Examples of heteroaryl        groups include, but are not limited to, (as numbered from the        linkage position assigned priority 1), 2-pyridyl, 3-pyridyl,        4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,        3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl,        isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl,        tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl,        benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl,        quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl.        Bivalent radicals derived from univalent heteroaryl radicals        whose names end in “-yl” by removal of one hydrogen atom from        the atom with the free valence are named by adding “-idene” to        the name of the corresponding univalent radical, e.g., a pyridyl        group with two points of attachment is a pyridylidene.        Heteroaryl does not encompass or overlap with aryl, cycloalkyl,        or heterocycloalkyl, as defined herein

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

By “heterocycloalkyl” is meant a single, non-aromatic ring, usually with3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. The ring may be saturated or have one or more carbon-carbondouble bonds. Suitable heterocycloalkyl groups include, for example (asnumbered from the linkage position assigned priority 1), 2-pyrrolidinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl,4-piperidyl, and 2,5-piperizinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo (=0) oroxide (—O⁻) substituents, such as piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteratoms independentlyselected from oxygen, sulfur, and nitrogen and is not aromatic.

As used herein, “modulation” refers to a change in activity as a director indirect response to the presence of compounds of Formula I, relativeto the activity of in the absence of the compound. The change may be anincrease in activity or a decrease in activity, and may be due to thedirect interaction of the compound with the kinesin, or due to theinteraction of the compound with one or more other factors that in turnaffect kinesin activity. For example, the presence of the compound may,for example, increase or decrease kinesin activity by directly bindingto the kinesin, by causing (directly or indirectly) another factor toincrease or decrease the kinesin activity, or by (directly orindirectly) increasing or decreasing the amount of kinesin present inthe cell or organism.

The term “sulfanyl” includes the groups: —S-(optionally substituted(C₁-C₆)alkyl), —S-(optionally substituted aryl), —S-(optionallysubstituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C₁-C₆alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)-(optionally substituted(C₁-C₆)alkyl), —S(O)-optionally substituted aryl), —S(O)-optionallysubstituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)-(optionally substituted(C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl), —S(O₂)-optionallysubstituted heteroaryl), —S(O₂)-(optionally substitutedheterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl, unless otherwise expressly defined, refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R_(b) is chosen from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom:

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R_(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R_(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl). Insome embodiments, a substituted alkoxy group is “polyalkoxy” or—O-(optionally substituted alkylene)-(optionally substituted alkoxy),and includes groups such as —OCH₂CH₂OCH₃, and residues of glycol etherssuch as polyethyleneglycol, and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of 2-20, such as 2-10, and for example, 2-5. Another substitutedalkoxy group is hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is an integerof 1-10, such as 1-4.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted refers toalkyl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from:

R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R_(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(e) wherein R^(d) is chosen from: hydroxy, optionallysubstitued alkoxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted acyl, optionally substitutedcarbamimidoyl, aminocarbonyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, andwherein R^(e) is chosen from: optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl, andwherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), sulfanyl (suchas SR^(b)), sulfinyl (such as —SOR^(a)), and sulfonyl (such as —SO₂R_(a)and —SO₂NR^(b)R^(c)),

where R_(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R_(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R_(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl); and

wherein optionally substituted acyl, optionally substitutedalkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds of Formula I include, but are not limited to, optical isomersof compounds of Formula I, racemates, and other mixtures thereof. Inthose situations, the single enantiomers or diastereomers, i.e.,optically active forms, can be obtained by asymmetric synthesis or byresolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high-pressure liquid chromatography (HPLC)column. In addition, compounds of Formula I include Z- and E-forms (orcis- and trans-forms) of compounds with carbon-carbon double bonds.Where compounds of Formula I exists in various tautomeric forms,chemical entities of the present invention include all tautomeric formsof the compound.

Chemical entities of the present invention include, but are not limitedto compounds of Formula I and all pharmaceutically acceptable formsthereof. Pharmaceutically acceptable forms of the compounds recitedherein include pharmaceutically acceptable salts, solvates, crystalforms (including polymorphs and clathrates), chelates, non-covalentcomplexes, prodrugs, and mixtures thereof. In certain embodiments, thecompounds described herein are in the form of pharmaceuticallyacceptable salts. Hence, the terns “chemical entity” and “chemicalentities” also encompass pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochloride, phosphate,diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, lactate, methanesulfonate,p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate,stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOH where n is0-4, and like salts. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium, and ammonium.

In addition, if the compound of Formula I is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of chemicalentities, for example ester or amide derivatives of the compounds ofFormula I. The term “prodrugs” includes any compounds that becomecompounds of Formula I when administered to a patient, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate, phosphate, and benzoate and likederivatives of functional groups (such as alcohol or amine groups) inthe compounds of Formula I.

The term “solvate” refers to the chemical entity formed by theinteraction of a solvent and a compound. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points.

The term “non-covalent complex” refers to the chemical entity formed bythe interaction of a compound and another molecule wherein a covalentbond is not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In certain embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

The term “antimitotic” refers to a drug for inhibiting or preventingmitosis, for example, by causing metaphase arrest. Some antitumour drugsblock proliferation and are considered antimitotics.

The term “therapeutically effective amount” of a chemical entity of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as ameliorationof symptoms, slowing of disease progression, or prevention of diseasee.g., a therapeutically effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to CENP-E inhibition. Insome embodiments, a therapeutically effective amount is an amountsufficient to reduce cancer symptoms. In some embodiments atherapeutically effective amount is an amount sufficient to decrease thenumber of detectable cancerous cells in an organism, detectably slow, orstop the growth of a cancerous tumor. In some embodiments, atherapeutically effective amount is an amount sufficient to shrink acancerous tumor.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of CENP-Eactivity” refers to a decrease in CENP-E activity as a direct orindirect response to the presence of at least one chemical entitydescribed herein, relative to the activity of CENP-E in the absence ofthe at least one chemical entity. The decrease in activity may be due tothe direct interaction of the chemical entity with CENP-E, or due to theinteraction of the chemical entity(ies) described herein with one ormore other factors that in turn affect CENP-E activity. For example, thepresence of the chemical entity(ies) may decrease CENP-E activity bydirectly binding to CENP-E, by causing (directly or indirectly) anotherfactor to decrease CENP-E activity, or by (directly or indirectly)decreasing the amount of CENP-E present in the cell or organism.

A “disease responsive to CENP-E inhibition” is a disease in whichinhibiting CENP-E provides a therapeutic benefit such as an ameliorationof symptoms, decrease in disease progression, prevention or delay ofdisease onset, or inhibition of aberrant activity of certain cell-types.

“Treatment” or “treating” means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methods ofthe invention can be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

The compounds of Formula I can be named and numbered in the mannerdescribed below using commercially available software. For example,using nomenclature software, such as MDL ISIS Draw Version 2.5 SP 1.,the compound:

can be named3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-[(2-hydroxyphenyl)methyl]-4-[(1-methylethyl)oxy]benzohydrazide.If that same compound is named with structure=name algorithm of ChemDrawUltra 9.0, the name isN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxybenzyl)-4-isopropoxybenzohydrazide.Compounds have also been named with Pipeline Pilot or Nomenclator™available from ChemInnovation Software, Inc.

The present invention is directed to a class of novel chemical entitiesthat are inhibitors of one or more mitotic kinesins. According to someembodiments, the chemical entities described herein inhibit the mitotickinesin, CENP-E, particularly human CENP-E. CENP-E is a plusend-directed microtubule motor essential for achieving metaphasechromosome alignment. CENP-E accumulates during interphase and isdegraded following completion of mitosis. Microinjection of antibodydirected against CENP-E or overexpression of a dominant negative mutantof CENP-E causes mitotic arrest with prometaphase chromosomes scatteredon a bipolar spindle. The tail domain of CENP-E mediates localization tokinetochores and also interacts with the mitotic checkpoint kinasehBubR1. CENP-E also associates with active forms of MAP kinase. Cloningof human (Yen, et al., Nature, 359(6395):536-9 (1992)) CENP-E has beenreported. In Thrower, et al., EMBO J., 14:918-26 (1995) partiallypurified native human CENP-E was reported on. Moreover, the studyreported that CENP-E was a minus end-directed microtubule motor. Wood,et al., Cell, 91:357-66 (1997)) discloses expressed Xenopus CENP-E in E.coli and that XCENP-E has motility as a plus end directed motor invitro. CENP-E See, PCT Publication No. WO 99/13061, which isincorporated herein by reference.

In some embodiments, the chemical entities inhibit the mitotic kinesin,CENP-E, as well as modulating one or more of the human mitotic kinesinsselected from HSET (see, U.S. Pat. No. 6,361,993, which is incorporatedherein by reference); MCAK (see, U.S. Pat. No. 6,331,424, which isincorporated herein by reference); RabK-6 (see U.S. Pat. No. 6,544,766,which is incorporated herein by reference); Kif4 (see, U.S. Pat. No.6,440,684, which is incorporated herein by reference); MKLP1 (see, U.S.Pat. No. 6,448,025, which is incorporated herein by reference); Kif15(see, U.S. Pat. No. 6,355,466, which is incorporated herein byreference); Kid (see, U.S. Pat. No. 6,387,644, which is incorporatedherein by reference); Mpp1, CMKrp, KinI-3 (see, U.S. Pat. No. 6,461,855,which is incorporated herein by reference); Kip3a (see, PCT PublicationNo. WO 01/96593, which is incorporated herein by reference); Kip3d (see,U.S. Pat. No. 6,492,151, which is incorporated herein by reference); andKSP (see, U.S. Pat. No. 6,617,115, which is incorporated herein byreference).

The methods of inhibiting a mitotic kinesin comprise contacting aninhibitor of the invention with one or more mitotic kinesin,particularly a human kinesin; or fragments and variants thereof. Theinhibition can be of the ATP hydrolysis activity of the mitotic kinesinand/or the mitotic spindle formation activity, such that the mitoticspindles are disrupted.

The present invention provides inhibitors of one or more mitotickinesins, in particular, one or more human mitotic kinesins, for thetreatment of disorders associated with cell proliferation. The chemicalentities compositions and methods described herein can differ in theirselectivity and are used to treat diseases of cellular proliferation,including, but not limited to cancer, hyperplasias, restenosis, cardiachypertrophy, immune disorders, fungal disorders and inflammation.

Accordingly, the present invention provides at least one chemical entitychosen from compounds of Formula I

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R₁ is chosen from optionally substituted aryl, optionally    substituted heterocycloalkyl, and optionally substituted heteroaryl;-   X is chosen from —CO and —SO₂—;-   R₂ is chosen from hydrogen and optionally substituted lower alkyl;-   W is chosen from —CR₄—, —CH₂CR₄—, and N;-   R₃ is chosen from —CO—R₇, hydrogen, optionally substituted alkyl,    optionally substituted heterocycloalkyl, optionally substituted    heteroaryl, cyano, sulfonyl, and optionally substituted aryl;-   R₄ is chosen from hydrogen and optionally substituted alkyl;-   R₅ is chosen from hydrogen, hydroxy, optionally substituted amino,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl; optionally substituted heteroaryl, and optionally    substituted lower alkyl;-   R₆ is chosen from hydrogen, optionally substituted alkyl, optionally    substituted alkoxy, optionally substituted aryloxy, optionally    substituted heteraryloxy, optionally substituted alkoxycarbonyl-,    aminocarbonyl-, optionally substituted aryl, optionally substituted    heteroaryl, optionally substituted cycloalkyl, and optionally    substituted heterocycloalkyl; and-   R₇ is chosen from optionally substituted lower alkyl, optionally    substituted aryl, hydroxy, optionally substituted amino, optionally    substituted aralkoxy, and optionally substituted alkoxy;-   provided that if W is N, then R₅ is not hydroxy or optionally    substituted amino, and R₆ is not optionally substituted alkoxy,    optionally substituted aralkoxy, optionally substituted    heteroaralkoxy, or optionally substituted amino.

In some embodiments, R₁ is optionally substituted aryl, or optionallysubstituted heteroaryl. In some embodiments, R₁ is optionallysubstituted aryl. In some embodiments, R₁ is optionally substitutedphenyl. In some embodiments, R₁ is phenyl substituted with one, two orthree groups independently selected from optionally substitutedheterocycloalkyl, optionally substituted alkyl, sulfonyl, halo,optionally substituted amino, sulfanyl, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy;acyl, hydroxy, nitro, cyano, optionally substituted aryl, and optionallysubstituted heteroaryl-. In some embodiments, R₁ is chosen from3-halo-4-isopropoxy-phenyl, 3-cyano-4-isopropoxy-phenyl,3-cyano-4-isopropylamino-phenyl, 3-chloro-4-isopropylamino-phenyl,3-cyano-4-trifluoroisopropyloxyphenyl,3-chloro-4-trifluoroisopropyloxyphenyl, 3-cyano-4-cylobutyloxyphenyl,3-chloro-4-cylobutyloxyphenyl, 3-cyano-4-cylopropyloxyphenyl,3-chloro-4-cylopropyloxyphenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-cyano-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-halo-4-isopropylamino-phenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl, and3-cyano-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl. In someembodiments, R₁ is 3-halo-4-isopropoxy-phenyl,3-cyano-4-isopropoxy-phenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-cyano-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-halo-4-isopropylamino-phenyl, 3-cyano-4-isopropylamino-phenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl, and3-cyano-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl.

In some embodiments, R₂ is hydrogen.

In some embodiments, X is —CO—.

In some embodiments, W is —CR₄— and R₄ is hydrogen.

In some embodiments, the compounds described herein possess apotentially chiral center, for example, when W is —CR₄—. The inventioncontemplates the use of pure enantiomers and mixtures of enantiomers,including racemic mixtures, although the use of a substantiallyoptically pure enantiomer will generally be preferred. The term“substantially optically pure” or “enantiomerically pure” means havingat least about 95% of the described enantiomer with no single impuritygreater than about 1% and particularly, at least about 97.5%enantiomeric excess. In some embodiments, the stereogenic center at W isas shown below:

In some embodiments, R₃ is —CO—R₇; hydrogen; optionally substitutedlower alkyl; cyano; sulfonyl; optionally substituted aryl; optionallysubstituted heteroaryl, or optionally substituted heterocycloalkyl. Insome embodiments, R₃ is optionally substituted lower alkyl or optionallysubstituted heteroaryl. In some embodiments, R₃ is optionallysubstituted lower alkyl. In some embodiments, R₃ is lower alkyl that isoptionally substituted with a hydroxy or a phosphate or acyl esterthereof, lower alkyl that is optionally substituted with a lower alkoxy,lower alkyl that is optionally substituted with an optionallysubstituted amino group, or lower alkyl that is optionally substitutedwith CO—R₈ where R₈ is hydroxy or optionally substituted amino. In someembodiments, R₃ is chosen from lower alkyl that is optionallysubstituted with a hydroxy or a phosphate or acyl ester thereof andlower alkyl that is optionally substituted with an optionallysubstituted amino group.

In some embodiments, R₅ is hydrogen, hydroxy, or optionally substitutedlower alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments, the compounds described herein possess apotentially chiral center when R₅ is not hydrogen. The inventioncontemplates the use of pure enantiomers and mixtures of enantiomers,including racemic mixtures, although the use of a substantiallyoptically pure enantiomer will generally be preferred. The term“substantially optically pure” or “enantiomerically pure” means havingat least about 95% of the described enantiomer with no single impuritygreater than about 1% and particularly, at least about 97.5%enantiomeric excess.

In some embodiments, R₆ is optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted cycloalkyl, or optionally substituted alkyl (suchas wherein the alkyl group is substituted with an optionally substitutedamino group or wherein the alkyl group is optionally substitutedcycloalkyl-). In some embodiments, R₆ is phenyl substituted with one ortwo of the following substituents: optionally substituted heteroaryl,optionally substituted amino, aralkoxy, halo, hydroxymethyl-, hydroxy,cyano, alkoxy, phenyl, phenoxy, methylenedioxy, ethylenedioxy, sulfonyl,aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy,and optionally substituted heterocycloalkyl.

Also provided is at least one chemical entity chosen from compounds ofFormula II

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₃, R₅, R₆, and Ware as described for compounds of Formula I and wherein

R₁₁ is optionally substituted heterocycloalkyl, optionally substitutedheteroaryl, optionally substituted lower alkyl, nitro, cyano, hydrogen,sulfonyl, or halo;

R₁₂ is hydrogen, halo, optionally substituted alkyl, optionallysubstituted amino, sulfanyl, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryloxy;and

R₁₃ is hydrogen, acyl, optionally substituted alkyl-, optionallysubstituted alkoxy, halo, hydroxy, nitro, cyano, optionally substitutedamino, alkylsulfonyl-, alkylsulfonamido-, alkylsulfonyl-, carboxyalkyl-,aminocarbonyl-, optionally substituted aryl or optionally substitutedheteroaryl-.

In some embodiments, R₁₁ is hydrogen, cyano, nitro, or halo. In someembodiments, R₁₁ is chloro or cyano.

In some embodiments, R₁₂ is optionally substituted lower alkoxy,optionally substituted lower alkyl, or optionally substituted amino-. Insome embodiments, R₁₂ is chosen from isopropoxy, isopropylamino,trifluoroisopropylamino, trifluoroisopropyloxy, cylobutyloxy, andcylopropyloxy. In some embodiments, R₁₂ is lower alkoxy,2,2,2-trifluoro-1-methyl-ethoxy, lower alkylamino or2,2,2-trifluoro-1-methyl-ethylamino. In some embodiments, R₁₂ ispropoxy, 2,2,2-trifluoro-1-methyl-ethoxy, propylamino, or2,2,2-trifluoro-1-methyl-ethylamino. In some embodiments, R₁₂ is not—O—(CH₂)_(n)NH₂ or —O—(CH₂)₄NH(CH₃) wherein n is 4 or 5.

In some embodiments R₁₁ and R₁₂, taken together, form an optionallysubstituted carbocyclic or heterocyclic ring. In some embodiments, R₁₁and R₁₂, taken together, form a methylenedioxy or ethylenedioxy ring. Insome embodiments, R₁₂ and R₁₃, taken together, form an optionallysubstituted carbocyclic or heterocyclic ring. In some embodiments, R₁₁and R₁₃, taken together, form an optionally substituted carbocyclic orheterocyclic ring.

In some embodiments, R₁₃ is hydrogen.

In some embodiments, R₂ and R₁₃, taken together, form an optionallysubstituted carbocyclic or heterocyclic ring, i.e., R₁, X, N, and R₂,taken together, form an optionally substituted carbocyclic orheterocyclic ring. In certain embodiments, a substituted2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl ring is formed, e.g.,

wherein the phenyl ring is optionally substituted. In other embodiments,a 4-oxo-4H-quinazolin-3-yl ring is formed, e.g.,

wherein the phenyl ring is optionally substituted. In certainembodiments, a 4-oxo-4H-pyridopyrimidin-3-yl ring is formed, e.g.,

wherein one or two of R, S, T, and U is nitrogen with the others being—CH and wherein the pyridine ring is optionally substituted.

Also provided is at least one chemical entity chosen from compounds ofFormula III

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₃, R₆, R₁₁, R₁₂,and R₁₃ are as described for compounds of Formula II.

Also provided is at least one chemical entity chosen from compounds ofFormula IV

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₆, R₁₁, R₁₂, andR₁₃ are as described for compounds of Formula III.

Also provided is at least one chemical entity chosen from compounds ofFormula V

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₃, R₁₁, R₁₂, andR₁₃ are as described for compounds of Formula III and wherein

R₁₄ is optionally substituted heterocycloalkyl or optionally substitutedheteroaryl; and

R₁₅ is chosen from hydrogen, halo, hydroxy, and lower alkyl.

In some embodiments, R₁₄ is chosen from

7,8-dihydro-imidazo[1,2-c][1,3]oxazin-2-yl,

3a,7a-dihydro-1H-benzoimidazol-2-yl,

imidazo[2,1-b]oxazol-6-yl,

oxazol-4-yl,

5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl,

1H-[1,2,4]triazol-3-yl,

2,3-dihydro-imidazol-4-yl,

1H-imidazol-2-yl,

imidazo[1,2-a]pyridin-2-yl,

thiazol-2-yl,

thiazol-4-yl,

pyrazol-3-yl, and

1H-imidazol-4-yl,

each of which is optionally substituted with one, two, or three groupschosen from optionally substituted lower alkyl, halo, acyl, sulfonyl,cyano, nitro, optionally substituted amino, and optionally substitutedheteroaryl.

In some embodiments, R₁₄ is chosen from

1H-imidazol-2-yl,

imidazo[1,2-a]pyridin-2-yl; and

1H-imidazol-4-yl,

each of which is optionally substituted with one or two groups chosenfrom optionally substituted lower alkyl, halo, and acyl.

In some embodiments, R₁₅ is hydrogen.

Also provided is at least one chemical entity chosen from compounds ofFormula VI

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₆, R₁₁, R₁₂, andR₁₃ are as described for compounds of Formula III and wherein

-   R₁₆ is chosen from halo, optionally substituted aryl, optionally    substituted heteroaryl, optionally substituted alkoxy, and    optionally substituted amino; and-   R₁₇ is chosen from hydrogen, lower alkoxy, halo, and lower alkyl.

In some embodiments, R₁₆ is chosen from optionally substituted phenyl,optionally substituted heteroaryl, optionally substituted lower alkoxy,and optionally substituted amino.

In some embodiments, R₁₆ is chosen from phenyl, optionally substitutedbenzyloxy, halo, optionally substituted 1H-imidazol-4-yl, optionallysubstituted 1H-benzo[d]imidazol-2-yl, and optionally substitutedcyclohexylmethoxy.

In some embodiments, R₁₇ is hydrogen.

Also provided is at least one chemical entity chosen from compounds ofFormula VII

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₂, R₆, R₁₁, R₁₂, andR₁₃ are as described for compounds of Formula III and wherein

-   R₉ is chosen from optionally substituted alkoxy, optionally    substituted cycloalkoxy, optionally substituted arylalkoxy,    optionally substituted amino and optionally substituted lower alkyl.

In some embodiments, R₉ is lower alkyl substituted with hydroxy oroptionally substituted amino. In some embodiments, R₉ is lower alkylsubstituted with hydroxy, amino, azetidino, N-methylamino, orN,N-dimethylamino.

Also provided is at least one chemical entity chosen from compounds ofFormula VIII

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof,

wherein R₁, X, W, R₃, R₄, R₆, and R₇ are as defined for compounds ofFormula I and wherein

-   R₂ and R₅, together with the atoms to which they are bound, form an    optionally substituted 5-7 membered heterocycle which optionally may    include one or two additional heteroatoms.

In some embodiments, R₂ taken together with R₅, form an optionallysubstituted pyrrolidinyl ring, or optionally substituted piperidinylring.

Also provided is at least one chemical entity chosen from compounds ofFormula IX

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof,

wherein R₁, X, W, R₂, R₃, R₄, and R₇ are as defined for compounds ofFormula I and wherein

-   R₅ and R₆, together with the atoms to which they are bound, form an    optionally substituted 5-7 membered heterocycle which optionally may    include one or two heteroatoms.

In some embodiments, R₅ and R₆, together with the atoms to which theyare attached, form an optionally substituted 2H-[1,2,3]triazol-4-yl; anoptionally substituted 1H-benzoimidazol-2-yl; an optionally substitutedpiperazinyl ring; an optionally substituted morpholinyl ring; or anoptionally substituted 1H-Imidazol-4-yl ring; an optionally substitutedisoxazol-4-yl ring.

Also provided is at least one chemical entity chosen from compounds ofFormula X

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁, X, W, R₄, R₅, R₆and R₇ are as defined for compounds of Formula I and wherein

-   R₂ and R₃, taken together with the atoms to which they are attached,    form an optionally substituted 3- to 7-membered heterocyclic ring.

In some embodiments, R₂ and R₃, taken together with the atoms to whichthey are attached, form an optionally substituted 3- to 7-memberedheterocyclic ring. In some embodiments, they form a pyrrolidinyl ring.

Also provided is at least one chemical entity chosen from compounds ofFormula XI

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein W, R₃, R₄, R₅, R₆ andR₇ are as defined for compounds of Formula I and wherein

R₁, X, N, and R₂, taken together, form a substituted2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl, 4-oxo-4H-quinazolin-3-yl, or4-oxo-4H-pyridopyrimidin-3-yl ring.

Also provided is at least one chemical entity chosen from compounds ofFormula XII

-   and pharmaceutically acceptable salts, solvates, chelates,    non-covalent complexes, prodrugs, and mixtures thereof, wherein R₁,    W, R₄, R₅, and R₆ are as defined for compounds of Formula I and    wherein-   —X—N(R₂)— is —C═N—; and    X taken together with R₃ forms an optionally substituted    heterocyclic ring;-   in each case, provided that if W is N, then R₅ is not hydroxy or    optionally substituted amino, and R₆ is not optionally substituted    alkoxy, optionally substituted aralkoxy, optionally substituted    heteroaralkoxy, or optionally substituted amino.

In certain embodiments, —X—N(R₂)— is —C═N—; and X taken together with R₃forms an optionally substituted heterocyclic ring, including but notlimited to 3H-[1,3,4]oxadiazol-2-one; 4,5-dihydro-oxazole; thiazole;imidazole; 3,5-dihydro-imidazol-4-one; or 3H-pyrimidin-4-one, each ofwhich is optionally substituted.

Also provided is at least one chemical entity chosen from compounds of

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof,

wherein R₁, X, W, R₂, R₄, R₅, and R₇ are as defined for compounds ofFormula I and wherein

-   R₃ and R₆, together with the atoms to which they are bound, form an    optionally substituted 5-7 membered heterocycle which optionally may    include one or two additional heteroatoms.

In some embodiments, R₃ and R₆, together with the atoms to which theyare attached, form an optionally substituted pyrrolidinyl ring, anoptionally substituted piperidinyl ring, or an optionally substituted1,2,3,4-tetrahydro-quinolin-3-yl ring.

Also provided is at least one chemical entity chosen from compoundsrecited in Table 1, 2, 3, 4, 5, or 6, and pharmaceutically acceptablesalts, solvates, chelates, non-covalent complexes, prodrugs, andmixtures thereof.

The compounds can be named and numbered using AutoNom version 2.1,ChemDraw Ultra 6.0, Cambridgesoft, Cambridge, Mass.; Struct<=>Namealgorithm of ChemDraw Ultra 9.0, Cambridgesoft, Cambridge, Mass. orISIS-DRAW. TABLE 1

N-{1-[4-(8-Bromo-5-methyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(isopropoxy)-benz- amide

N-{1-[4-(8-ethyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-isopropenyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(1-Acetylamino-propyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(iso-propoxy)-benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-[1-(4-{2-[1-(Acetyl-methyl-amino)-eth-yl]-1-ethyl-1H-imidazol-4-yl}-ben-zyl)-3-hydroxy-propyl]-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-pro-pyl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-{1-[4-(8-chloro-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-trifluoromethyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-[1-(Acetyl-methyl-amino)-eth-yl]-1-ethyl-1H-imidazol-4-yl]-ben- zyl}-3-hydroxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-{1-[4-(8-Bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-iso-propyl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl]-ben-zyl}-ethyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-[1-(3-methyl-ureido)-eth- yl]-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-Acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(1-Acetylamino-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-{1-[4-(8-chloro-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-Bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(1-(iso- propoxycarbonylamino)-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-carbamoyl-propyl}-3-cyano-4-isopropoxy- benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-(1-hy- droxy-ethyl)-imi-dazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-cyano-4-isopropoxy-benz-amide

N-{1-[4-(8-acetyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-(1-hy- droxy-ethyl)-imi-dazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-cyclo-propylmethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-{1-[4-(8-isopropyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-formylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{3-fluoro-4-[2-(1-methyl-1hydroxy-ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-{1-[2-fluoro-4-(8-methyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-acetyl-1-(3-hy- droxypropyl)-1H-imidazol-4-yl]ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-{1-[4-(8-acetyl-5-methyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-Acetylamino-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-[1-[4-(2-acetyl-1-ethyl-1H-imi- dazol-4-yl)-benzyl]-2-(2-hydroxy-acetylamino)-ethyl]-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{4-[2-t-butyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-2-di-methylcarbamoyl-ethyl)-3-chloro-4-iso- propoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-cyano-4-isopropoxy- benzamide

N-(1-{2-fluoro-4-[2-t-butyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-carbamoyl-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-isobutyryl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-(2-hydroxy-ethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-methyl-1-hydroxy- ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-[1-[4-(8-Bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-ethyl]-3-cy- ano-4-isopropoxy-benzamide

N-(1-{4-[2-(3-hydroxy-pent-3-yl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi- dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-(2,2,2-trifluoroethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide

N-[1-[4-(2-acetyl-1-ethyl-1H-imi- dazol-4-yl)-benzyl]-2-(2-hydroxy-acetylamino)-ethyl]-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-acetyl-1-(2-methoxyethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl]-ben-zyl}-ethyl)-3-cyano-4-isopropoxy- benzamide

N-(2-(2-amino-propionyl- amino)-1-{4-[8-(1-hydroxy-ethyl)-imi-dazo[1,2-a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-(5,5-dimethyl-7,8-dihydro- imidazo[1,2-c][1,3]oxazin-2-yl)-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-isobutyryl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-(8-methyl-5,6,7,8-tetrahydro- imidazo[1,2-a]py-ridin-2-yl)-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-acetyl-1-propyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-2-carbamoyl-ethyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(2-(2-amino-propionylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-hydroxy-2-methyl- propyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-(1-{3-fluoro-4-[2-(1-hydroxy-1-meth-yl-ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{4-[2-propionyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-(2,2,2-trifluoroethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-formylamino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]py-ridin-2-yl]-benzyl}-ethyl)-3-chloro-4-iso- propoxy-benzamide

N-(3-fluoro-1-{4-[2-(1-hydroxy-1-meth-yl-ethyl)-1-methyl-1H-imidazol-4-yl]-ben- zyl}-3-hydroxy-propyl)-3-cy-ano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-{1-[4-(8-chloro-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-pro-pyl}-3-chloro-4-isopropoxy- benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-cyano-4-isopropoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-carbamoyl-butyl)-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-carbamoyl-propyl}-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-carbamoyl-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-ethyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-propionyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(2-(2-hydroxy-acetylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-hydroxyimino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-(3-hydroxy-pent-3-yl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-acetyl-1-(2,2,2-trifluoro-ethyl)-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(2-(3-hydroxy-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-(2-(2-hydroxy-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-ureido-ethyl]-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-carbamoyl-propyl}-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-hydroxypropyl)-1-ethyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-2-carbamoyl-ethyl)-3-chloro-4-isopropoxy- benzamide

N-(2-(2-hydroxy-acetylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(1-{4-[2-isobutyryl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi-dazo[1,2-a]pyridin-2-yl)-benzyl]-3-carba- moyl-propyl}-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-{1-[4-(8-bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-carbamoyl-propyl}-3-chloro-4-isopropoxy-benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-bromo-imi-dazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-{1-[4-(8-(carbamoyl)-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi- dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(acetyl-amino)-ethyl]-3-cyano-4-iso- propoxy-benzamide

N-{1-[2-fluoro-4-(8-methyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-chloro-4-iso- propoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{4-[2-(1-Acetylamino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-carbamoyl-propyl)-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(4-methyl-3a,7a-dihydro-1H-benzo-imidazol-2-yl)-benzyl]-3-hydroxy- propyl}-3-chloro-4-iso-propoxy-benzamide

N-(1-{2,3,5,6-tetrafluoro-4-[2-t-butyl-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-(1-fluoro-prop-2-yl- oxy)-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl- ethyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-{1-[4-(8-(3,5-dimethyl-isoxazol-4-yl)-imi-dazo[1,2-a]pyridin-2-yl)-ben- zyl]-3-hydroxy-propyl}-3-cyano-4-iso-propoxy-benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi-dazo[1,2-a]pyridin-2-yl)-benzyl]-3-car- bamoyl-propyl}-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-2-methyl- propyl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1-methyl-eth- yl)-1-methyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-isopropenyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-isopropyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-trifluoromethyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-(2-{4-[2-t-butyl-1-methyl-1H-imi-dazol-4-yl]-phenyl}-1-(1H-[1,2,4]tri- azol-5-yl)-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-{1-[3-chloro-4-(8-methyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-{1-[4-(3-methyl-imidazo[2,1-b]oxa- zol-6-yl)-benzyl]-3-hydroxy-butyl}-3-cyano-4-isopropoxy- benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]py- ridin-2-yl]-benzyl}-ethyl)-3-chlor-o-4-isopropoxy-benzamide

N-(1-hydroxy-1-{4-[2-t-butyl-1-meth- yl-1H-imidazol-4-yl]-phenyl}-4-hy-droxy-butyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-2-(N,N-di-methylcarbamoyl)-ethyl)-3-chloro-4-iso- propoxy-benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-[1-[4-(8-bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-(3-methyl-ureido)-ethyl]-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-[1-(acetylamino)-propyl]-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(3-methyl-ureido)-ethyl]-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(cyclopropylcarbonyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-cyclobutoxy- benzamide

N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-2-car- bamoyl-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(1-methyl-ureido)-ethyl]-3-chloro-4-isopropoxy- benzamide

N-{1-[4-(8-hydroxymethyl- imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-t-butyl-1-(2-hydroxyethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-[1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-ureido-ethyl]-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(methylsulfonyl)-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-ethyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-[1-[4-(8-bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-ureido-ethyl]-3-cyano-4-isopropoxy- benzamide

N-(2-{4-[2-t-butyl-1-methyl-1H-imi-dazol-4-yl]-phenyl}-1-(5-methyl-[1,2,4]oxa-diazol-3-yl)-ethyl)-3-cyano-4-iso- propoxy-benzamide

N-{1-[2,6-difluoro-4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy- droxy-propyl}-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-1-methyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-formylamino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-car- bamoyl-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(2-(2-amino-propionylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]py- ridin-2-yl]-benzyl}-ethyl)-3-cy-ano-4-isopropoxy-benzamide

N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-2-meth-ylcarbamoyl-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-2-di-methylcarbamoyl-ethyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-{1-[4-(8-cyano-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(2-(2-amino-2-methyl- propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-2,3-dichloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi- dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-chloro-4-iso- propoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-ethyl]-3-cy- ano-4-isopropoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-3-hy-droxycarbamoyl-propyl]-3-cyano-4-iso- propoxy-benzamide

N-{1-[4-(5-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-(isopropylamino)-benz- amide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(formyl-amino)-ethyl]-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-(2-Acetyl-oxazol-4-yl)-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(2-(2-amino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(2-(2-hydroxy-2-methyl- propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-(2-{4-[5-t-butyl-1-methyl-1H-[1,2,4]tri-azol-3-yl]-phenyl}-1-([1,2,4]oxa- diazol-3-yl)-ethyl)-3-cyano-4-iso-propoxy-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-2-amino-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-car-bamoyl-propyl)-3-chloro-4-(2,2,2-tri- fluoro-1-methyl-ethoxy)-benzamide

N-(2-(2-amino-3-hydroxy- propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-{1-[2,6-difluoro-4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy- droxy-propyl}-3-chloro-4-iso-propoxy-benzamide

N-{1-[4-(8-amino-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-acetyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-isopropoxy- benzamide

N-{1-[4-(8-(1-methyl-1-hydroxy- ethyl)-imidazo[1,2-a]pyridin-2-yl)-ben-zyl]-3-hydroxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(1-(meth- oxycarbonylamino)-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[2-(1-(meth- oxycarbonylamino)-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]py- ridin-2-yl]-benzyl}-ethyl)-3-cy-ano-4-isopropoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-carbamoyl-ethyl]-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-(ethoxycarbonylamino)-eth-yl)-1-ethyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benz- amide

N-{1-[4-(imidazo[1,2-a]pyridin-2-yl)-ben-zyl]-3-hydroxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(2-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-phenyl}-1-(1H-imi-dazol-2-yl)-ethyl)-3-cyano-4-iso- propoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-(isopropylamino)-benz- amide

N-[1-[4-(8-bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-(3-methyl-ureido)-ethyl]-3-chloro-4-isopropoxy- benzamide

N-{1-[4-(8-(1-hydroxypropyl)-imi- dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-chloro-4-iso- propoxy-benzamide

N-[1-[4-(2-t-butyl-1-(2-aminoethyl)-1H-imi- dazol-4-yl)-benzyl]-2-(2-hy-droxy-acetylamino)-ethyl]-3-chloro-4-iso- propoxy-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-(3-hydroxy-ureido)-ethyl]-3-cyano-4-isopropoxy- benzamide

N-(2-(3-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(2-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-phenyl}-1-([1,2,4]oxa-diazol-3-yl)-ethyl)-3-cyano-4-iso- propoxy-benzamide

N-(2-(2-amino-3-hydroxy- propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-chloro-4-isopropoxy-benzamide

N-{1-[4-(8-nitro-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy- benzamide

N-{1-[2,6-difluoro-4-(8-methyl-5,6,7,8-tet- rahydro-imidazo[1,2-a]py-ridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-acetyl-1-ethyl-1H-imi- dazol-4-yl]-benzyl}-2-meth-ylcarbamoyl-ethyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(2-(2-amino-propionylamino)-1-{4-[8-meth-yl-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-[1-[4-(8-bromo-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-2-(2-oxo-imidazolidinyl)-ethyl]-3-chloro-4-iso- propoxy-benzamide

N-[1-[4-(2-(1-hydroxy-1-methyl- ethyl)-1-methyl-1H-imidazol-4-yl)-ben-zyl]-2-(2-amino-propionylamino)-eth- yl]-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-acetyl-1-butyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-eth-yl-1H-imidazol-4-yl]-benzyl}-2-carba- moyl-ethyl)-3-chloro-4-iso-propoxy-benzamide

N-(1-{4-[4-t-butyl-1H-imidazol-2-yl]-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[2-(2,2-dimethyl-propyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-cyano-4-iso-propoxy-benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]pyri- din-2-yl]-benzyl}-ethyl)-3-cy-ano-4-isopropoxy-benzamide

N-(1-{4-[2-isobutyryl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(1-{3-fluoro-4-[2-(1-hydroxy-1-meth-yl-ethyl)-1-methyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-chlor- o-4-isopropoxy-benzamide

N-(1-{4-[2-(1-hydroxy-ethyl)-1-meth- yl-1H-imidazol-4-yl]-benzyl}-3-hy-droxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[5-t-butyl-1-methyl-1H-[1,2,4]tri- azol-3-yl]-benzyl}-3-hy-droxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-[1-[4-(2-t-butyl-1-(2-amino-ethyl)-1H-imi-dazol-4-yl)-benzyl]-2-(2-di- methylamino-acetylamino)-ethyl]-3-chlor-o-4-isopropoxy-benzamide

N-[1-{4-[1-(3-(t-bu- toxycarbonylamino)-propyl)-2-t-bu-tyl-2,3-dihydro-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl]-3-chloro-4-iso- propoxy-benzamide

N-(2-(2-hydroxy-propionylamino)-1-{4-[8-(1-hy-droxy-ethyl)-imidazo[1,2-a]py- ridin-2-yl]-benzyl}-ethyl)-3-cy-ano-4-isopropoxy-benzamide

N-(2-(acetylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}-eth- yl)-3-cyano-4-isopropoxy-benzamide

N-(1-{4-[2-t-butyl-1-(2-aminoethyl)-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-(1-methoxyimino-ethyl)-1-met-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-iso-propoxy-benzamide

N-{1-[4-(8-(3-hydroxy-propenyl)-imi-dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy- droxy-propyl}-3-cyano-4-iso-propoxy-benzamide

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-car- bamoyl-imidazo[1,2-a]py-ridin-2-yl]-benzyl}-ethyl)-3-cy- ano-4-isopropoxy-benzamide

N-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imi-dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-meth- yl-ethoxy)-benzamide

N-(2-(2-amino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-cyano-4-isopropoxy-benzamide

N-(2-{4-[2-acetyl-1-methyl-1H-imi-dazol-4-yl]-phenyl}-1-(5-methyl-[1,2,4]oxa-diazol-3-yl)-ethyl)-3-cyano-4-iso- propoxy-benzamide

N-[1-[4-(2-t-butyl-1-methyl-1H-imi- dazol-4-yl)-benzyl]-2-hydroxy-3-azi-do-propyl]-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[5-t-butyl-4-methyl-1H-imi- dazol-2-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-(1-hydroxy-ethyl)-imi- dazo[1,2-a]pyridin-2-yl)-benzyl]-3-hy-droxy-propyl}-3-cyano-4-iso- propoxy-benzamide

N-(1-{4-[5-t-butyl-4-methyl-1H-imi- dazol-2-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy- benzamide

N-(1-{4-[2-(1-acetylamino-ethyl)-1-meth-yl-1H-imidazol-4-yl]-benzyl}-3-hy- droxy-propyl)-3-chloro-4-(2,2,2-tri-fluoro-1-methyl-ethoxy)-benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-2-amino-butyl)-3-cyano-4-isopropoxy- benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-cyano-4-isopropoxy- benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-2-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamide

N-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-ben- zyl}-ethyl)-3-chloro-4-isopropoxy-benzamide

N-(1-{4-[2-acetyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropylamino- benzamide

N-(1-{4-[2-t-butyl-1H-imidazol-4-yl]-ben-zyl}-3-hydroxy-propyl)-3-cyano-4-iso- propoxy-benzamide

N-{1-[4-(8-methyl-imidazo[1,2-a]py- ridin-2-yl)-benzyl]-3-hydroxy-propyl}-2-nitro-4-trifluoromethyl- benzamide

N-(1-{4-[2-t-butyl-1-methyl-1H-imi- dazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-iodo-4-isopropoxy- benzamide

-   (S)-3-chloro-N-(1-(4-(1-ethyl-2-(2-hydroxypropan-2-yl)-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-4-isopropoxybenzamide-   (S)-N-(1-(4-(2-acetyl-1-ethyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide-   N-((S)-1-(4-(2-(1-acetamidoethyl)-1-ethyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide-   3-chloro-N-((S)-1-(4-(1-ethyl-2-(2-hydroxypropan-2-yl)-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-4-(1,1,1-trifluoropropan-2-yloxy)benzamide-   N-((S)-1-(4-(2-(1-acetamidoethyl)-1-ethyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-(1,1,1-trifluoropropan-2-yloxy)benzamide-   (S)-N-(1-(4-(2-acetyl-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide-   3-chloro-N-((S)-4-hydroxy-1-(4-(8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)phenyl)butan-2-yl)-4-isopropoxybenzamide-   (S)-3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide-   3-chloro-N-((S)-1-(2-(dimethylamino)acetamido)-3-(4-(8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide;-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-(D-Alanylamino)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-[(N,N-dimethylglycyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   N-((1R)-4-Amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-4-oxobutyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-((1R)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-2-[(N,N-dimethylglycyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide;-   N-((1R)-1-{[4-(2-Acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-[(1R)-4-Amino-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-4-oxobutyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(hydroxyacetyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(N,N-dimethylglycyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({[(2R)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-[(Aminocarbonyl)amino]-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-{(1S)-2-[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(2-oxotetrahydro-1(2H)-pyrimidinyl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-{(1S)-2-[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(2-oxohexahydro-1H-1,3-diazepin-1-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-[(Aminocarbonothioyl)amino]-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-3-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]propyl}phenyl)imidazo[1,2-a]pyridine-8-carboxamide-   N-((1S)-2-[(Aminosulfonyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   (3S)-3-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}butanoic    acid-   N-[(1S)-2-[(Aminosulfonyl)amino]-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(1H-Benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[5-(methyloxy)-1H-benzimidazol-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(5-chloro-1H-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-3-hydroxy-1-{[4-(4-methyl-1H-benzimidazol-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   Ethyl    2-(4-{(2S)-2-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-1H-benzimidazole-5-carboxylate-   2-(4-{(2S)-2-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-1H-benzimidazole-5-carboxylic    acid-   N-((1S)-3-Amino-1-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}propyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-1-{[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(8-Chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-hydroxyimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxamide-   Ethyl    2-(4-{(2S)-2-[({3-cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxylate-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-nitroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(8-Aminoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-8-carboxamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-1-({4-[8-(Aminomethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-(2-hydroxyethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-1-({4-[1-[2-(Acetylamino)ethyl]-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1R)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   N-[(1R)-4-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-4-oxobutyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide-   N-[(1R)-4-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-4-oxobutyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(3-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-1-{[4-(3-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-4-[(1-methylethyl)oxy]-N-[(1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-(4-morpholinylmethyl)ethyl]benzamide-   3-Chloro-N-((1S)-2-(4-hydroxy-1-piperidinyl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-(3-hydroxy-1-pyrrolidinyl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-4-[(1-methylethyl)oxy]-N-((1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-{[(2,2,2-trifluoroethyl)amino]methyl}ethyl)benzamide-   3-Chloro-N-((1S)-2-[(2-hydroxyethyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-1-{[4-(8-ethyl-5-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   Methyl    (3S)-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[(phenylcarbonyl)amino]phenyl}butanoate-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[(phenylcarbonyl)amino]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-{(1S)-1-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)methyl]-3-hydroxypropyl}-4-[(1-methylethyl)oxy]benzamide-   Phenylmethyl    (4-{(2S)-2-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)carbamate-   3-Chloro-N-((1S)-3-hydroxy-1-{[4-({[2-(methylamino)phenyl]carbonyl}amino)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   N-(4-{(2S)-2-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-4-pyridinecarboxamide-   3-Chloro-N-[(1S)-1-({4-[(cyclohexylcarbonyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({4-[(3,3-dimethylbutanoyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[(phenylacetyl)amino]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-{(1S)-3-hydroxy-1-[(4-{[(phenylamino)carbonyl]amino}phenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(1-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-6-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   2,3-Dichloro-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-3-Hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]-3-nitrobenzamide-   3-Chloro-N-[(1S)-2-[(hydroxyacetyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({[(2R)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({[(2S)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-2-(D-Alanylamino)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl-]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   (3S)-3-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[(phenylcarbonyl)amino]phenyl}butanoic    acid-   3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-6-ylphenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)imidazo[1,2-a]pyridin-6-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-2-ylphenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyrimidin-2-ylphenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-3-hydroxy-1-{[4-(5-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-3-hydroxy-1-{[4-(7-methylimidazo[1,2-a]pyrimidin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-{(1S)-3-hydroxy-1-[(4-imidazo[2,1-b][1,3]thiazol-6-ylphenyl)methyl]butyl}-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}butyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-1-{[4-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}-3-hydroxybutyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-1-{[4-(1,1-dioxido-2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}-3-hydroxybutyl)-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-1-({4-[1-(3-Aminopropyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-4-[(1-methylethyl)oxy]-N-[(1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]benzamide-   3-Cyano-N-[(1S)-1-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(4-isoxazolyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide-   Ethyl    (2E)-3-[2-(4-{(2S)-2-[({3-cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridin-8-yl]-2-propenoate-   (2E)-3-[2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridin-8-yl]-2-propenoic    acid-   N-{(1S)-1-[(4-{8-[(1E)-3-Amino-3-oxo-1-propen-1-yl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-1-({4-[8-(3-Amino-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[4-(3-chloro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-1-{[4-(3-Chloro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-1-({3-fluoro-4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-hydroxy-1-{[5-(8-methylimidazo[1,2-a]pyridin-2-yl)-2-pyridinyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-hydroxy-1-{[5-(8-methylimidazo[1,2-a]pyridin-2-yl)-2-thienyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2-fluorophenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2,6-difluorophenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({2-chloro-4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({5-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2-pyridinyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[2-chloro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[2-chloro-4-(8-chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[2,5-difluoro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-1-{[3-chloro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-(methylamino)-3-oxopropyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-({[(phenylamino)carbonyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-({[(ethylamino)carbonyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   N-[(1S)-2-(Aminosulfonyl)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-((1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-{[(methylsulfonyl)amino]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-{(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-[({[(2-hydroxyethyl)amino]carbonyl}amino)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide-   N-[(S)-1-[4-(2-tert-Butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-(2-methoxy-ethanoylamino)-ethyl]-3-cyano-4-isopropoxy-benzamide-   (4R)-4-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}pentanoic    acid-   3-Cyano-N-{(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-[(2-oxo-1-imidazolidinyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-Amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   N-((1S)-2-(Acetylamino)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-((1S)-2-{[(2R)-2-hydroxypropanoyl]amino}-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide-   3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-Cyano-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide-   3-chloro-N-((S)-4-hydroxy-1-(4-(1-methyl-2-((R)-1-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)phenyl)butan-2-yl)-4-isopropoxybenzamide-   3-chloro-N-((S)-4-hydroxy-1-(4-(1-methyl-2-((R)-1-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)phenyl)butan-2-yl)-4-(1,1,1-trifluoropropan-2-yloxy)benzamide-   3-chloro-N-((S)-4-hydroxy-1-(4-(1-methyl-2-((R)-1-(2-oxooxazolidin-3-yl)ethyl)-1H-imidazol-4-yl)phenyl)butan-2-yl)-4-isopropoxybenzamide-   3-chloro-N-((S)-4-hydroxy-1-(4-(1-methyl-2-((R)-1-(2-oxooxazolidin-3-yl)ethyl)-1H-imidazol-4-yl)phenyl)butan-2-yl)-4-(1,1,1-trifluoropropan-2-yloxy)benzamide

Particular compounds include those shown in the following tables: TABLE2

R₁₁ R₃ R₈ R₉ R₅ R₁₀ Cl Phenyl H H 4- H isoprop oxy-3- chloro- benzoyl-amino- Cl Hydroxymethyl- 2-tert-Butyl-3H-imidazol-4-yl H H H ClHydroxymethyl- Benzylamino- H H H Cl H 2-tert-Butyl-3H-imidazol-4-yl H HH Cl Hydroxymethyl- 4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl ClHydroxymethyl- 5-tert-Butyl-4H-[1,2,4]triazol- H H H 3-yl ClHydroxymethyl- 1H-Benzoimidazol-2-yl H H H Cl Hydroxymethyl-4-tert-Butyl-imidazol-1-yl H H H Cl H 1H-Benzoimidazol-2-yl H H H ClMethoxymethyl- 2-tert-Butyl-3H-imidazol-4-yl H H H Cl 3- Benzyloxy- H HH Hydroxypropyl- Cl H 2-Methylamino- H H H benzoylamino- ClHydroxymethyl- Benzyloxy- Cl H H Cl Hydroxymethyl- Benzyloxy- Hydroxy- HH methyl- Cl Hydroxymethyl- 4-tert-Butyl-1H-imidazol-2-yl H H H Cl2-Hydroxyethyl- Benzyloxy- H H H Cl H Benzyloxy- H H H Cl Hydroxymethyl-t-Butoxycarbonyl-amino- H H H Cl H OH H H H Cyano Hydroxymethyl-Benzyloxy- Cyano H H Cl Hydroxymethyl- Benzyloxy- Cyano H H Cl H Amino HH H Cyano 2-Hydroxyethyl- 4-Cyano-benzyl- H H H Cl Hydroxymethyl-4-tert-Butyl-1-methyl-1H- H H H imidazol-2-yl Cyano Hydroxymethyl-Benzyloxy- Cl H H Cl Hydroxymethyl- H H H H Cl H H H OH H Cl H HMethoxy- H H Cl H F H H H Cl Pyridin-4-yl- Phenyl H H H methyl-amino-methyl- Cl Cyano H H H H Cl Hydroxymethyl- Benzyloxy- Cl H H ClDimethylamino- Phenyl H H H methyl- Cl Pyridin-3-yl- Phenyl H H Hmethyl-amino- methyl- Cl Hydroxymethyl- 2-Methylamino-benzoylamino H H HCl Hydroxymethyl- 2-tert-Butyl-2H-tetrazol-5-yl H H H Cl (1,3-Dioxo-1,3-4-Isopropyl-4,5-dihydro- H H H dihydro- oxazol-2-yl isoindol-2-yl)-methyl- Cl Aminomethyl- Phenyl H H H Cl (1,3-Dioxo-1,3- Phenyl H H Hdihydro- isomdol-2-yl)- methyl- Cl Phenyl H Amino H H Cl Hydroxymethyl-Hydroxy H H H Cl Aminomethyl- H H H H Cl 1H-Tetrazol-5-yl H H H H ClDimethylamino- H H H H Cl H Phenoxy- H H H Cl H Cl H H H Cl H H H MorphoH lino Cl H Methoxy H H H Cl Hydroxymethyl- Cl H H H Cl HMethylenedioxy- H H Cl H H Cl H H Cl Pyridin-2- Phenyl H H Hylmethyl-amino- methyl- Cl Cyano-(pyridin- Phenyl H H H 2-ylmethylamino)- methyl- Cl 2-Hydroxyethyl- Phenyl H H H aminomethyl- ClHydroxymethyl- H H OH H Cl Aminoethyl- Phenyl H H H aminomethyl- ClMethoxymethyl- H H H H Cl Chloromethyl- Phenyl H H H Cl Hydroxymethyl-Phenyl H H H Cl Hydroxymethyl- Benzyloxy- H H H Cl H Aminosulfonyl- H HH Cl Hydroxymethyl- Cyano H H H Cl Hydroxymethyl- Carbamyl- H H H Cli-propylamino- Cyclopropyl-methoxy- H H H methyl- Cl Methylamino- PhenylH H H methyl- Cl Methylamino- Hydroxymethyl- H H H methyl- ClAminomethyl- Cyclopropyl-methoxy- H H H Cl Ethylamino- Phenyl- H H Hmethyl- Cl Benzylamino- Phenyl H H H methyl- Cl N-(2- Phenyl H H HHydroxypropyl)- aminomethyl- Cl 2-Hydroxyethyl-5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl Cl Hydroxymethyl-2-tert-Butyl-1-methyl-1H- H H H imidazol-4-yl Cl Methyl-2-tert-Butyl-1H-imidazol-4-yl H H H Cl Hydroxymethyl-5-Methyl-4-trifluoromethyl- H H H 1H-imidazol-2-yl Cl Hydroxymethyl-1-tert-Butyl-2-methyl-1H- H H H imidazol-4-yl Cyano 2-Hydroxyethyl-3-Hydroxy-2-methyl-propoxy- H H H Cl 2-Aminoethyl-4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl Cyano 2-Hydroxyethyl-5-tert-Butyl-isoxazol-3-yl H H H Cyano Hydroxymethyl-1H-Benzoimidazole-2-yl H H H Cyano Hydroxymethyl- 1-Methoxymethyl-1H- HH H benzoimidazole-2-yl Cyano Hydroxymethyl- 4-tert-Butyl-5-methyl-1H- HH H imidazol-2-yl Cl Hydroxymethyl- Cyclopropylmethoxy- H H H Cl HTert-Butoxycarbonyl- H H H Cl Aminomethyl- 2-tert-Butyl-1H-imidazol-4-ylH H H Cyano Methylamino- 5-tert-Butyl-4-methyl-1H- H H H imidazol-2-ylCyano H Benzyloxy- H H H Cyano 2-Hydroxyethyl- 5-tert-Butyl-4-methyl-1H-H H H imidazol-2-yl Cyano Hydroxymethyl- Benzyloxy- F H H ClHydroxymethyl- Benzyloxy- Dimethyl- H H carbamoyl Cl Hydroxymethyl-Benzyloxy- Carboxy- H H Cl Hydroxymethyl- Benzyloxy- F H H CyanoHydroxymethyl- Benzyloxy- Cl H H Cyano Hydroxymethyl-2-tert-Butyl-1-methyl-1H- H H H imidazol-4-yl Cyano Methyl-2-tert-Butyl-1H-imidazol-4-yl H H H Cyano Hydroxymethyl-1-tert-Butyl-2-methyl-1H- H H H imidazol-4-yl Cyano Hydroxymethyl-Benzyloxy- Carboxy H H Cyano 2-Hydroxyethyl- 2-Cyano-benzyloxy- H H HCyano 2-Hydroxyethyl- 3-Cyano-benzyloxy- H H H Cyano 2-Aminoethyl-4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl Cyano Hydroxymethyl-Benzyloxy- Dimethyl- H H carbamoyl- Cyano Hydroxymethyl- Benzyloxy-Methyl- H H carbamoyl- Cl Amino- Benzyloxy- H H H Cl 2-4-tert-Butyl-5-methyl-1H- H H H (Acetylamino)- imidazol-2-yl ethyl-Cyano 2-Hydroxyethyl- Benzyloxy- H H H Cl Aminomethyl-5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl Cyano 2-4-tert-Butyl-5-methyl-1H- H H H (Methoxycarbon imidazol-2-ylylamino)-ethyl- Cyano Hydroxymethyl- Benzyloxy- Acetylamino- H H Cl H2-Methylamino- H H H benzoylamino- Cl H Benzyloxy- H H H Cyano2-Aminoethyl- 4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl CyanoHydroxymethyl- Benzyloxy- Hydroxy H H Cl Aminomethyl-1H-Benzoimidazol-2-yl H H H Cl Hydroxymethyl- Benzyloxy- H H H ClHydroxymethyl- Hydroxy H H H Cl H Amino H H H Cl H Tert-Butyoxycarbonyl-H H H Cl H Hydroxy H H H Cl H Nitro H H H Cl Hydroxymethyl-4-tert-Butyl-1H-imidazol-2-yl H H H Cl Hydroxymethyl- Benzyoxy-Dimethyl- H H carbamoyl- Cl Hydroxymethyl- 4-tert-Butyl-1-methyl-1H- H HH imidazol-2-yl Cyano Hydroxymethyl- Benzyloxy- Carboxy- H H Cyano2-Hydroxyethyl- 4-Cyanobenzyloxy- H H H Cyano 2-Hydroxyethyl-3-Cyanobenzyloxy- H H H Cyano Hydroxymethyl- Benzyloxy- Cyano H H ClAmino Benzyloxy- H H H Cyano 2-Hydroxyethyl- 2-Cyanobenzyloxy- H H HCyano Hydroxymethyl- 3-tert-Butyl-3H-imidazol-4-yl H H H CyanoHydroxymethyl- Benzyloxy- Acetylamino- H H Cyano H Benzyloxy- H H H ClHydroxymethyl- Benzyloxy- F H H Cyano 2-Hydroxyethyl-5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl Cl Hydroxymethyl-2-tert-Butyl-3H-imidazol-4-yl H H H Cl Hydroxymethyl- Benzyloxy-Dimethyl- H H amino-methyl- Cyano Hydroxymethyl- Benzyloxy- Cl H H CyanoHydroxymethyl- Benzyloxy- Fluoro H H Cl Hydroxymethyl-4-tert-Butyl-imidazol-1-yl H H H Cl Methoxymethyl-2-tert-Butyl-3H-imidazol-4-yl H H H Cl H 1H-Benzoimidazol-2-yl H H H ClAminomethyl- 5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl ClHydroxymethyl- Benzyloxy- Cyano H H Cl Hydroxymethyl- Benzyloxy-Carboxy- H H Cyano Aminomethyl- 5-tert-Butyl-4-methyl-1H- H H Himidazol-2-yl Cyano Hydroxymethyl- Benzyloxy- Methyl- H H carbamoyl-Cyano Hydroxymethyl- Benzyloxy- Dimethyl- H H carbamoyl- Iodo2-Hydroxyethyl- 5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl Cl2-Hydroxyethyl- 5-tert-Butyl-4-methyl-1H- H H H imidazol-2-yl ClHydroxymethyl- 1-tert-Butyl-2-methyl-1H- H H H imidazol-4-yl Cyano2-Hydroxyethyl- Hydroxy- H H H Cyano 2-Hydroxyethyl-3-Hydroxy-2-methyl-propoxy- H H H Cyano Hydroxymethyl-2-tert-Butyl-1-methyl-1H- H H H imidazol-4-yl Cl Hydroxymethyl-5-Methyl-4-trifluoromethyl- H H H 1H-imidazol-2-yl Cyano Hydroxymethyl-5-Methyl-4-trifluoromethyl- H H H 1H-imidazol-2-yl Cl Methyl-2-tert-Butyl-1H-imidazol-4-yl H H H Cyano Hydroxymethyl-1-tert-Butyl-2-methyl-1H- H H H imidazol-4-yl Cl H2-tert-Butyl-3H-imidazol-4-yl H H H Cl 2-Aminoethyl-4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl Cl Aminomethyl-Cyclopropyl-methoxy- H H H Cl Isopropylamino- Cyclopropyl-methoxy- H H Hmethyl- Cyano Hydroxymethyl- 4-tert-Butyl-5-methyl-1H- H H Himidazol-2-yl Cl Hydroxymethyl- 2-tert-Butyl-2H-tetrazol-5-yl H H H ClHydroxymethyl- Benzyloxy- Hydroxy- H H methyl- Cl Aminomethyl-Carbamoyl- H H H Cl Hydroxymethyl Benzylamino- H H H Cl Hydroxymethyl2-Methylamino- H H H benzoylamino- Cl Aminomethyl-4-Isopropyl-4,5-dihydro- H H H oxazol-2-yl Cl 2-Hydroxyethyl- Benzyloxy-H H H Cl Hydroxymethyl- 5-tert-Butyl-4H-[1,2,4]triazol- H H H 3-yl ClHydroxymethyl- 4-tert-Butyl-5-methyl-1H- H H H imidazol-2-yl ClHydroxymethyl- Tert-Butoxycarbonylamino- H H H Cl Hydroxymethyl-Cyclopropylmethoxy- H H H Cl (1,3-Dioxo-1,3- Carbamoyl- H H H dihydro-isoindol-2-yl)- methyl- Cl Hydroxymethyl- Cyano H H H Cl 3- Benzyloxy- HH H Hydroxypropyl- Cyano Hydroxymethyl- 1-Methoxymethyl-1H- H H Hbenzoimidazole-2-yl Cl (1,3-Dioxo-1,3- 1H-benzoimidazole-2-yl H H Hdihydro- isoindol-2-yl)- methyl- Cyano Hydroxymethyl-2-tert-Butyl-3H-imidazol-4-yl H H H Cyano 2-Hydroxyethyl- Hydroxy- H H HCyano Hydroxymethyl- 1H-benzoimidazole-2-yl H H H Cl Hydroxymethyl-2H-Tetrazol-5-yl H H H Cl Aminomethyl- 2-tert-Butyl-1H-imidazol-4-yl H HH Cyano 2-Hydroxyethyl- Benzyloxy- H H H Cl Hydroxymethyl- Benzyloxy H HH Cl Hydroxymethyl- 2-tert-Butyl-1-methyl-1H- H H H imidazol-4-yl Cl2-Hydroxyethyl- 5-tert-Butyl-[1,2,4]oxadiazol- H H H 3-ylmethoxy- Cl H HH H Cl Cl H H H H Meth oxy- Cl 4-Methyl- Phenyl H H H piperazin-1-ylmethyl- Cl (2-Amino- Phenyl H H H ethylamino) cyano-methyl- Cl(Piperazin-1-yl)- Phenyl H H H cyano-methyl- Cl Cyano-(2- Phenyl H H Hhydroxy-2- phenyl- ethylamino)- methyl- Cl (2-Hydroxy-2- Phenyl H H Hphenyl- ethylamino)- methyl- Cl Hydroxymethyl- 4-Isopropyl-4,5-dihydro-H H H oxazol-2-yl Cl Aminomethyl- 1H-benzoimidazole-2-yl H H H Cl1H-Tetrazol-5-yl Phenyl H H H Cl Morpholin-4- Phenyl H H H ylmethyl- Cl[2-(2-Oxo- Phenyl H H H imidazolidin-1- yl)-ethylamino]- methyl-

TABLE 3

R₁₁ R₇ R₅ R₆ Cl Methylamino- H 4-(1H-Benzoimidazol-2-yl)-phenyl- Cl(Pyridin-4-yl)methyl- H Phenyl amino- Cl Methylamino- H Thiophen-3-yl ClAmino H 4-Hydroxyphenyl- Cl Methylamino- H 3-Chiorophenyl- ClMethylamino- H 4-(N═N═N)-phenyl- Cl Methylamino- H Benzo[b]thiophen-3-ylCl Methylamino H Pyridin-2-yl Cl Methylamino H Pyridin-3-yl ClMethylamino- H Cyclohexyl- Cl Methylamino- H Naphth-1-yl ClIsopropylamino- H Phenyl Cl Methylamino- H 4-biphenyl- Cl Methylamino- HThiazol-4-yl Cl Methylamino- H 4-biphenyl- Cl Amino H 4-biphenyl- ClMethoxy- H 4-biphenyl- Cl Methylamino- H Phenyl Cl Methylamino H4-Isobutylsulfamoyl-phenyl- Cl (1-Carbamoyl-2-methyl- H 4-biphenylpropyl)-amino- Cl Carbamoylmethyl-amino- H 4-tert-butoxyphenyl- ClMethyl-amino- H 4-Isopropylsulfamoyl-phenyl- Cl Amino H4-Cyclohexyloxy-phenyl- Cl Methyl-amino H4-(1-Oxo-1H-phthalazin-2-yl)-phenyl- Cl Methyl-amino H4-(2-Oxo-piperidin-1-yl)-phenyl- Cl Methyl-amino H4-Dibenzylamino-phenyl- Cl Methylamino- H 4-Chlorophenyl Cl Methylamino-H Pyridin-4-yl Cl Methylamino- H 5-Methoxy-1H-indol-3-yl Cl Amino HPhenyl Cl OH H Phenyl Cl Methylamino- H Phenyl Cl Carbamoylmethyl-amino-H 4-Isobutyrylamino-phenyl- Cl Carbamoylmethyl-amino- H4-(3-Methyl-butyrylamino)-phenyl- Cl Carbamoylmethyl-amino- H4-(2,2-Dimethyl-propionylamino)-phenyl- Cl Carbamoylmethyl-amino- H4-[(Morpholine-4-carbonyl)-amino]-phenyl- Cl Methylamino H4-(Benzylamino)-phenyl- Cl Carbamoylmethyl-amino- H4-(Cyclohexanecarbonyl-amino)-phenyl- Cl Methylamino- H4-(Benzyloxy)-phenyl- Cl Carbamoylmethyl-amino- H4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- Phenyl- Cl Tert-Butoxy- H4-(4-Morphohn-4-yl-[1,2,5]thiadiazol-3- yloxy)-phenyl- Cl Methoxy- H4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl- ClCarbamoylmethyl-amino- H 4-(Cyclopropylmethoxy)-phenyl- Cl Amino- H4-(2-Oxo-3-phenyl-cyclopentyloxy)-phenyl- Cl Amino- H4-(3-Bromo-[1,2,4]thiadiazol-5-yloxy)- phenyl- Cl Methylamino H2-Phenyl-1H-benzoimidazole-5-yl Cl Ethoxy- H4-(4-tert-Butyl-5-methyl-1H-imidazol-2-yl)- phenyl- Cyano Methylamino- H4-Benzyloxy-phenyl- Cl Methylamino- H4-[(3-Fluorophenyl)-carbonylamino]- cyclohexyl- Cl Methylamino- H4-(1H-Benzoimidazol-2-yl)-phenyl- Cl Methylamino H 4-Benzyloxy-phenyl-Cl Methylamino H 4-(1H-Benzoimidazol-2-yl)-phenyl- Cl Amino H4-(1-Methoxymethyl-1H-benzoimidazol-2- yl)-phenyl- Cl Methylamino- H4-(t-Butoxycarbonyl)-aminomethyl-phenyl- Cl Methylamino- H4-(4-Aminomethyl-benzoylamino)-phenyl- Cl Methoxy- H4-(Methoxycarbonyl)-phenyl- Cl Methylamino- H4-(4-Allylcarbamoyl-1H-imidazol-2-yl)- phenyl- Cl Methylamino H4-[(6-Morpholin-4-yl-pyridine-3-carbonyl)- amino]-phenyl- Cl MethylaminoH 4-(4-Chloro-benzoylamino)-phenyl- Cl Methylamino H(3-tert-Butyl-ureido)-cyclohexan-4-yl Cl Methylamino H4-(4-Dimethylcarbamoyl-1H-imidazol-2- yl)-phenyl- Cl Methylamino H(1H-Benzoimidazol-2-yl)-cyclohexan-4-yl Cl Methylamino HCarbamoyl-cyclohexan-4-yl Cl Methylamino H4-(2-Chloro-benzoyl)-amino-phenyl- Cl Methylamino H4-[4-(Morpholine-4-carbonyl)-1H-imidazol- 2-yl]-phenyl- MethoxyMethylamino H 4-Benzyloxy-phenyl- Cl Methylamino HCarbamoyl-cyclohexan-4-yl Cl Methylamino H4-(3-Chloro-benzoyl)-amino-phenyl- Cl Methylamino Htert-Butoxycarbonyl-amino-cyclohexan-4-yl Cl Methylamino HBenzylcarbamoyl-cyclohexan-4-yl Cl Methylamino H4-[4-(1-Hydroxy-1-methyl-ethyl)-thiazol-2- yl]-phenyl- Cl Methylamino H4-[4-(2-Carboxy-1,1-dimethyl-ethyl)-1H- imidazol-2-yl]-phenyl ClMethylamino- H 4-tert-Butoxycarbonylamino-phenyl- Cl Methylamino Htert-Butoxycarbonylamino-cyclohexan-4-yl Cl Methylamino H(4-tert-Butyl-1H-imidazol-2-yl)-cyclohexan- 4-yl Cl Methylamino H4-[4-(2-Ethoxycarbonyl-1,1-dimethyl- ethyl)-1H-imidazol-2-yl]-phenyl- ClMethylamino- H 4-Aminocyclohexanyl- Cl Methylamino H4-(Pyridin-3-ylcarbamoyl)-cyclohexanyl Cl Methylamino H4-(4-Oxo-1,4-dihydro-quinazolin-2-yl)- phenyl- Cl Methylamino H4-[4-(1H-Pyrazol-3-ylcarbamoyl)-1H- imidazol-2-yl]-phenyl- ClMethylamino H 4-(4-Propylcarbamoyl-1H-imidazol-2-yl)- phenyl- ClMethylamino H 4-(4-Cyclopropylcarbamoyl-1H-imidazol-2- yl)-phenyl-Fluoro Methylamino H 4-Benzyloxyphenyl- Cl Methylamino H4-(4-Trifluoromethyl-1H-imidazol-2-yl)- phenyl- Cl Methylamino H4-(4-Cyclopropylmethyl-carbamoyl-1H- imidazol-2-yl)-phenyl- ClMethylamino H 4-Benzoimidazol-1-yl-phenyl- Cl Methylamio H4-[4-(2-Methoxy-ethylcarbamoyl)-1H- imidazol-2-yl]-phenyl- ClMethylamino H 4-(4-Isopropylcarbamoyl-1H-imidazol-2- yl)-phenyl- ClMethylamino H 4-[4-(2-Methoxy-phenyl)-1H-imidazol-2- yl]-phenyl- ClMethylamino H 4-(Pyridin-4-ylcarbamoyl)-cyclohexanyl- Cl Methylamino H4-[4-(3-Methoxy-propylcarbamoyl)-1H- imidazol-2-yl]-phenyl- ClMethylamino H 4-(4-Hydroxymethyl-thiazol-2-yl)-phenyl- Cl Methylamino H4-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]- phenyl- Cl Methylamino H4-(Isopropylcarbonyl-amino)-cyclohexanyl- Cl Methylamino H4-[4-(Pyridin-4-ylcarbamoyl)-1H-imidazol- 2-yl]-phenyl- Cl Methylamino H4-[4-(3-Methyl-butylcarbamoyl)-1H- imidazol-2-yl]-phenyl- Cl MethylaminoH 4-[4-(3-Methoxy-phenylcarbamoyl)-1H- imidazol-2-yl]-phenyl- ClMethylamino H 4-Isobutoxycarbonylamino-cyclohexanyl- Cl Methylamino H4-(2-Fluoro-benzoylamino)-cyclohexanyl- Cl Methylamino H4-[4-(2-Dimethylamino-ethylcarbamoyl)- 1H-imidazol-2-yl]-phenyl- ClMethylamino H 4-(6-Isopropyl-4-oxo-1,4-dihydro- pyrimidin-2-yl)-phenyl-Cl Methylamino H 4-(4-Morpholin-4-yl-benzoylamino)- phenyl- Cl Amino H4-Hydroxycyclohexanyl- Cl Methylamino- H4-(4-Ethoxycarbonyl-1H-imidazol-2-yl)- phenyl- Cl Methylamino H4-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-phenyl- Cl Methiamino H4-Cyanophenyl- Cl (Pyridin-3-yl-methyl)- H Phenyl amino Cl Methylamino Hp-tolyl- Cl Methylamino H 3-Hydroxyphenyl- Cl Methiamino HThiophen-2-yl- Cl Methylamino H 2-Hydroxyphenyl- Cl Methylamino H4-Biphenyl- Cl Methylamino H 1-Methyl-1H-imidazol-4-yl Cl Methylamino H4-(4-Cyanophenyl)-phenyl- Cl Methylamino H 3-Methoxyphenyl- Cl(Furan-2-yl-methyl)- H Phenyl amino- Cl Methylamino H4-(2-Hydroxyphenyl)-phenyl- Cl Methylamino H 2-Fluorophenyl- ClMethylamino H 4-tert-butyiphenyl- H Methylamino H 4-Biphenyl- ClMethylamino H Naphth-2-yl Cl Methylamino H 4-Biphenyl- ClIndan-2-yl-amino- H Phenyl Cl Methylamino H 4-(3-Fluorophenyl)-phenyl ClMethylamino H 4-(4-Hydroxyphenoxy)-phenyl- Cl Methylamino H4-(3-Methoxyphenyl)-phenyl- Cl Pyridin-2-yl-amino- H Phenyl ClMethylamino H 1H-[1,2,4]triazol-1-yl Cl (2-Methyl-propyl)-amino- HPhenyl Cl Methylamino H 4-(2-Fluorophenyl)-phenyl- Cl Methylamino HIsoquinolin-3-yl Cl Methylamino H 3-Fluorophenyl- Cl Dimethylamino H4-Biphenyl- Cl Methylamino H 4-(Phenylcarbonyl)-phenyl- Cl Methylamino H4-Fluorophenyl- Cl OH H 4-Biphenyl- Cl Ethyl amino H 4-Biphenyl- ClMethylamino H 4-Hydroxybenzyl- Cl Methylamino Methyl Hydroxy ClMethylamino H 1H-Indol-2-yl Cl Amino H Isopropyl Cl Methylamino H1H-Pyrrolo[2,3-b]pyridin-2-yl Cl 2-(Dimethylamino)-ethyl- H Phenylamino- Cl Methylamino H 2-Chlorophenyl Cl (3-Hydroxypropyl)-amino HPhenyl Cl Methylamino Methyl Phenyl Cl Amino H4-(Pyrimidin-2-yloxy)-phenyl- Cl Methylamino H Benzyl- Cl Methylamino H4-Carboxyphenyl- Cl Methylamino H 4-Bromophenyl- Cl Methylamino HBenzyl- Cl Methylamino H 4-(tert-butoxycarbonylaminomethyl)- phenyl- ClMethylamino H 4-Aminophenyl- Cl Pyridin-2-ylmethyl- H Phenyl amino- ClMethylamino H 4-Aminomethyl-phenyl- Cl Methylamino H4-Acetylamino-phenyl- Cl Methylamino H 4-(Thiophen-2-yl)-phenyl- ClMethylamino H 4-(Hydroxy-phenyl-methyl)-phenyl- Cl Methylamino H2-Bromophenyl- Cl Amino H 4-(5-Methyl-isoxazol-3-ylmethoxy)-phenyl- ClMethylamino H 4-(4-Methylphenyl)-phenyl- Cl Methylamino H4-(3-Hydroxyphenyl)-phenyl- Cl Methylamino H 4-Benzyloxy-phenyl- ClMethylamino H 4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl Cl Methylamino H4-Hydroxyphenyl- Cl Cyclopropylamino- H Phenyl Cl Methoxy H4-Hydroxyphenyl Cl (Tetrahydro-furan-2-yl- H Phenyl methyl)-amino ClMethylamino H 4-Trifluoromethyiphenyl- Cl Methylamino H4-[(6-Morpholin-4-yl-pyridine-3-carbonyl)- amino]-phenyl- Cl MethylaminoH 4-(3-Oxo-[1,2,4]triazolo[4,3-a]pyridin-2- yl)-phenyl- Cl Methylamino H4-[4-(tert-Butoxycarbonylamino-methyl)- benzoylamino]-phenyl- ClMethylamino H 4-(4-Aminomethyl-benzoylamino)-phenyl- Cl Methylamino H4-(4-Carboxy-thiazol-2-yl)-benzoic acid Cl Methylamino H4-(6-Oxo-1,6-dihydro-pyrimidin-2-yl)- phenyl Cl Methylamino H4-Bromophenyl Cl Methylamino H4-[4-(2-Methoxy-ethylcarbamoyl)-thiazol-2- yl]-phenyl Cl Methylamino H4-[4-(Isopropylcarbamoyl)-thiazol-2-yl]- phenyl Cl Methylamino H4-[4-(Dimethylcarbamoyl)-thiazol-2-yl]- phenyl Cl Methylamino H4-[4-(4-Methyl-piperazine-1-carbonyl)- thiazol-2-yl]-phenyl ClMethylamino H 4-[4-(Morpholine-4-carbonyl)-thiazol-2-yl]- phenyl ClMethylamino H 4-Benzyloxy-3-methoxyphenyl Cl Methylamino H4-(2-Furan-2-yl-thiazol-4-yl)-phenyl Cl 1-Carbamoyl-2-methyl- H4-Biphenyl- propylamino Cl Methylamino H 4-(Dibenzylamino)-phenyl- ClMethylamino H 4-(1-Oxo-1H-phthalazin-2-yl)-phenyl Cl Methylamino H4-(Benzylamino)-phenyl- Cl Methylamino H 4-(2-Oxo-piperidin-1-yl)-phenylCl Carbamoyl-methylamino- H 4-[(Morpholine-4-carbonyl)-amino]-phenyl ClCarbamoyl-methylamino- H 4-[(Cyclohexylcarbonyl)-amino]-phenyl ClCarbamoyl-methylamino- H 4-(3-Methyl-butyrylamino)-phenyl Cl Amino H4-(Piperidin-4-ylcarbamoylmethoxy)-phenyl Cl Amino H4-(sec-Butylcarbamoyl-methoxy)-phenyl Cl Methylamino H4-Isobutylsulfamoyl-phenyl Cl Methylamino H 4-Isopropylsulfamoyl-phenylCl Amino H 4-(4-Chloro-[1,2,5]thiadiazol-3-yloxy)- phenyl ClCarbamoyl-methylamino H 4-(tert-Butoxycarbonyl)-phenyl ClCarbamoyl-methylamino H 4-(4-Morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-phenyl Cl Amino H 4-(Cyclohexyloxy)-phenyl Cl Methylamino H4-(4-Oxo-4H-quinazolin-3-yl)-phenyl Cl Tert-Butoxy H4-(4-Morpholin-4-yl-[1,2,5]thiadiazol-3- yloxy)-phenyl Cl Amino H4-(3-Bromo-[1,2,4]thiadiazol-5-yloxy)- phenyl Cl Amino H4-(2-Oxo-1-phenyl-pyrrolidin-3-yloxy)- phenyl Cl Methylamino H4-(4-Fluoro-benzoylamino)-phenyl Cl Methylamino H4-(3-Fluoro-benzoylamino)-phenyl Cl Carbamoyl-methylamino H4-(1H-Benzoimidazol-2-yl)-phenyl Cl Hydroxy H4-(1H-Benzoimidazol-2-yl)-phenyl Cl Methoxy H4-(1H-Benzoimidazol-2-yl)-phenyl Cl Carbamoyl-methylamino H4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl Cl Hydroxy H4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl Cl Methoxy H4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl Cl Carbamoyl-methylaminoH 4-(Cyclopropylmethoxy)-phenyl- Cl Tert-Butoxy H4-(Pyridin-3-ylmethoxy)-phenyl

TABLE 4

R₁₁ T R₁₄ R₆ Cl —CH₂NH— Aminomethyl- 4-(Cyclopropyl-methoxy)-phenyl- Cl—CH₂— Methylamino- 3-Chlorophenyl- Cl —CH₂NH— 2-Hydrazinocarbonyl-4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl- phenyl Cl —CH₂NH—Aminomethyl- 4-(1H-Benzoimidazol-2-yl)-phenyl Cl —CH₂NH— Aminomethyl-4-(Carbamoyl)-phenyl Cl —CH₂NH— Aminomethyl-4-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)- phenyl Cl —CH₂NH— Aminomethyl-4-(Cyclopropylmethoxy)-phenyl- Cl —CH₂O— Methylamino4-(2-tert-Butyl-1H-imidazol-4-yl)-phenyl Cl —CH₂NH— Methylamino4-(2-tert-Butyl-1H-imidazol-4-yl)-phenyl Cyano —CH₂NH— Methylamino4-(4-tert-Butyl-5-methyl-1H-imidazol-2- yl)-phenyl Cl —CH₂O— Methoxy-4-(2-tert-Butyl-1H-imidazol-4-yl)-phenyl Cl —CH₂NH— Methyl 4-Biphenyl Cl—CH₂NH— Methyl Phenyl Cl —CH₂CH₂— Methylamino 4-Benzyloxy-phenyl- Cl—CH₂— Methylamino 2-Chlorophenyl- Cl —CH₂— Methylamino Phenyl Cl —CH₂—Methylamino 4-Biphenyl- Cl —CH₂CH₂— Methylamino 4-Benzyloxy-phenyl- ClAbsent Amino Tert-butoxycarbonyl- Cl —CH₂NH— Aminomethyl-4-Carbamoyl-phenyl- Cl —CH₂NH— Aminomethyl-4-(1H-Benzoimidazol-2-yl)-phenyl- Cl —CH₂O— 2-(Methyl-amino)-phenyl-4-[(2-Methylamino-benzoyl)-amino]- phenyl- Cl Absent AminoBenzyloxycarbonyl- Cl —CH₂— OH 4-Biphenyl-

TABLE 5

W R₃ R₆ CH Hydrogen Tert-butoxycarbonyl- CH 2-(Methylcarbamoyl)-ethyl-Phenyl CH 2-(Carboxy)-ethyl- Phenyl —CH₂CH— Carboxy Phenyl NMethylamino-carbonyl- 2-Phenyl-3H-benzoimidazol- 5-yl C Hydroxymethyl-Hydroxy C Hydrogen Methylamino-carbonyl C Hydrogen(Dimethylamino)-carbonyl- C Amino-carbonyl- (Methylsulfanyl)-methyl- NMethylamino-carbonyl- 4-Benzyloxy-3-methyoxy- phenyl- NMethylamino-carbonyl- 3-Benzyloxy-phenyl- N Methylamino-carbonyl-4-(Benzoylamino)-phenyl- N Methylamino-carbonyl- 4-Bromophenyl- NMethylamino-carbonyl- 2-Phenyl-thiazole-4-yl N Methylamino-carbonyl-Phenyl N Methylamino-carbonyl- 5-Phenyl-[1,2,4]oxadiazol- 3-yl NMethylamino-carbonyl- 4-(1H-Benzoimidazol-2-yl)- phenyl- CHMethyl-sulfonylamino- 4-Biphenyl- methyl-

TABLE 6N-[2-(4-Benzyloxy-phenyl)-1-methylcarbamoyl-ethyl]-2,3-dichloro-4-isopropoxy-benzamide3-(3H-Imidazol-4-yl)-2-(4-trifluoromethyl-benzenesulfonylamino)-propionicacid N-(2-Biphenyl-4-yl-1-methylcarbamoyl-ethyl)-benzamideN-(1-Carbamoyl-2-phenyl-ethyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide;N-(1-Carbamoyl-2-phenyl-ethyl)-4-fluoro-benzamide4-[2-(4-tert-Butoxy-3-chloro-benzoylamino)-2-methylcarbamoyl-ethyl]-benzoicacid tert- butyl esterN-[2-(4-Benzyloxy-phenyl)-1-methylcarbamoyl-ethyl]-3-chloro-4-isopropylamino-benzamide2-Benzyl-3-(3-chloro-4-isopropoxy-benzoylamino)-propionic acidNaphthalene-2-carboxylic acid[2-(4-benzyloxy-phenyl)-1-methylcarbamoyl-ethyl]-amideQuinoline-7-carboxylic acid[2-(4-benzyloxy-phenyl)-1-methylcarbamoyl-ethyl]-amide1-Isopropyl-1H-benzoimidazole-5-carboxylic acid[2-(4-benzyloxy-phenyl)-1- methylcarbamoyl-ethyl]-amide5-Biphenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-phenyl)-3,5-dihydro-imidazol-4-one5-Biphenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-phenyl)-3H-imidazole-4-carboxylicacid methyl ester5-Biphenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-phenyl)-3H-imidazole-4-carboxylicacid methylamide4-(4-{4-[2-(3-Chloro-4-isopropoxy-phenyl)-4,5-dihydro-oxazol-4-ylmethyl]-phenoxy}-[1,2,5]thiadiazol-3-yl)-morpholine4-(4-Benzyloxy-benzyl)-2-(3-chloro-4-isopropoxy-phenyl)-4,5-dihydro-oxazole3-Biphenyl-4-ylmethyl-5-(3-chloro-4-isopropoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one1-(3-Chloro-4-isopropoxy-benzoyl)-3-(4-iodo-phenyl)-pyrrolidine-2-carboxylicacid methylamide3-(4-Bromo-phenyl)-1-(3-chloro-4-isopropoxy-benzoyl)-pyrrolidine-2-carboxylicacid methyl ester3-Biphenyl-4-yl-1-(3-chloro-4-isopropoxy-benzoyl)-pyrrolidine-2-carboxylicacid methylamide1-(3-Chloro-4-isopropoxy-benzoyl)-3-phenyl-piperidine-2-carboxylic acidmethylamide1-(3-Chloro-4-isopropoxy-benzoyl)-4-phenyl-piperidine-2-carboxylic acidmethylamide1-(3-Chloro-4-isopropoxy-benzoyl)-4-phenyl-piperazine-2-carboxylic acidmethylamide(2-Biphenyl-4-ylmethyl-aziridin-1-yl)-(3-chloro-4-isopropoxy-phenyl)-methanone3-Biphenyl-4-yl-N-carbamoylmethyl-2-(6-chloro-7-isopropoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-propionamide3-Biphenyl-4-yl-N-carbamoylmethyl-2-(6-chloro-7-isopropoxy-4-oxo-4H-quinazolin-3-yl)-propionamide3-Biphenyl-4-yl-N-carbamoylmethyl-2-(8-chloro-7-isopropoxy-4-oxo-4H-quinazolin-3-yl)-propionamide3-Chloro-4-isopropoxy-N-(1,2,3,4-tetrahydro-quinolin-3-yl)-benzamide3-Chloro-4-isopropoxy-N-(4-phenyl-pyrrolidin-3-yl)-benzamide3-Chloro-4-isopropoxy-N-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-benzamide3-Chloro-4-isopropoxy-N-(1-methyl-1H-imidazol-4-ylmethyl)-benzamide3-Chloro-4-isopropoxy-N-(2-phenoxy-ethyl)-benzamideN-[2-(4-Benzyl-piperazin-1-yl)-ethyl]-3-chloro-4-isopropoxy-benzamideN-(1H-Benzoimidazol-2-ylmethyl)-3-chloro-4-isopropoxy-benzamide3-Chloro-4-isopropoxy-N-(5-methyl-2-phenyl-2H-[1,2,3]triazol-4-ylmethyl)-benzamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)acetamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)carboxamideN-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N,N-dimethylbutanamideN-((1S)-1-{[3-chloro-4-(8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-3-hydroxy-1-{[4-(8-methyl-6-oxo(5H,7H,8H-imidazo[1,2-a]1,4-diazaperhydroin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)ethoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylethoxy)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylamino)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(ethylamino)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)[(methylethyl)amino]carboxamideN-[(1S)-1-({4-[8-((1S)-1-hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamideN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)(3-chloro-4-cyclopropoxyphenyl)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)(methylamino)carboxamideN-{(1R)-1-[4-(4-{(2S)-2-[(3-chloro-4-cyclopropoxyphenyl)carbonylamino]-4-hydroxybutyl}phenyl)-1-methylimidazol-2-yl]ethyl}acetamideN-((1S)-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-[(1S)-3-hydroxy-1-({4-[8-((hydroxyimino)ethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)propyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl](3-chloro-4-cyclopropoxyphenyl)carboxamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N,N-dimethylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N-methylbutanamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl dihydrogen phosphateN-[(1S)-1-({4-[8-(aminoethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[8-(hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}propyl)-2-pyrrolidinylacetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamideN-[1-({4-[2-((1R)-1-aminopropyl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylamino)carboxamideN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(2,2,2-trifluoro-isopropoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl]carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)carboxamide((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]propyl)-2-azetidinylacetamideN-{1-[(4-{2-[(1R)-1-(2-oxopyrrolidinyl)ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[2-(hydroxyethyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-azetidinylacetamide((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxycarboxamideN-[1-({4-[2-((2R)-1-acetylpyrrolidin-2-yl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamidemethyl (2R)-2-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}pyrrolidinecarboxylateN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]propyl)-2-(dimethylamino)acetamideN-((1R)-3-carbamoyl-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)-N-methylacetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxy-N-methylcarboxamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl 2-(dimethylamino)acetateN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[4-((1S)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl (2S)-2-amino-3-methylbutanoateN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamideN-{1-[(4-{2-[(1R)-1-(2-oxo(1,3-oxazolidin-3-yl))ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-(phenylmethoxy)propyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)-N-methylacetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)ethoxy-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamideN-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamideN-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamideN-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]carboxamideN-{(1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-[(4-bromophenyl)methyl]ethyl}[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-{[4-(2-bromoacetyl)phenyl]methyl}ethyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-1-{[4-(2-bromoacetyl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-carbamoylethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamide(3R)-3-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-3-(acetylamino)propanoicacidN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)isoxazol-5-ylcarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-methoxyacetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-furylcarboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamide methyl1-(biphenyl-4-ylmethyl)-2-(3-chloro-4-isopropoxybenzoyl)hydrazinecarboxylate1-(biphenyl-4-ylmethyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide1-(4-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide1-(4-(benzyloxy)-3-methoxybenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide1-(4-benzamidobenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamideN-(2-amino-2-oxoethyl)-1-(4-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)hydrazinecarboxamide1-(3-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide2-(3-chloro-4-isopropoxybenzoyl)-N-methyl-1-((2-phenyl-3H-benzo[d]imidazol-5-yl)methyl)hydrazinecarboxamide1-(4-(1H-benzo[d]imidazol-2-yl)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide1-(4-bromobenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamideN′-(4-(benzyloxy)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide3-chloro-N′-(4-(4-fluorobenzyloxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-cyano-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazideN′-(4-(1H-benzo[d]imidazol-2-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide3-chloro-N′-(4-(cyclohexylmethoxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide3-cyano-N′-(4-(cyclohexylmethoxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(3-hydroxypropyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-cyano-N′-(3-hydroxypropyl)-4-isopropoxybenzohydrazideN′-(4-(benzyloxy)benzyl)-3-chloro-N′-(2-cyanoethyl)-4-isopropoxybenzohydrazideN′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxybenzyl)-4-isopropoxybenzohydrazideN′-(4-biphenylylmethyl)-3-chloro-N′-(hydrazinocarbonyl)-4-[(1-methylethyl)oxy]benzohydrazideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)acetamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)carboxamideN-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N,N-dimethylbutanamideN-((1S)-1-{[3-chloro-4-(8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-3-hydroxy-1-{[4-(8-methyl-6-oxo(5H,7H,8H-imidazo[1,2-a]1,4-diazaperhydroin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)ethoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylethoxy)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylamino)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(ethylamino)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)[(methylethyl)amino]carboxamideN-[(1S)-1-({4-[8-((1S)-1-hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamideN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)(3-chloro-4-cyclopropoxyphenyl)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)(methylamino)carboxamideN-{(1R)-1-[4-(4-{(2S)-2-[(3-chloro-4-cyclopropoxyphenyl)carbonylamino]-4-hydroxybutyl}phenyl)-1-methylimidazol-2-yl]ethyl}acetamideN-((1S)-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-[(1S)-3-hydroxy-1-({4-[8-((hydroxyimino)ethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)propyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl](3-chloro-4-cyclopropoxyphenyl)carboxamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N,N-dimethylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N-methylbutanamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl dihydrogen phosphateN-[(1S)-1-({4-[8-(aminoethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[8-(hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}propyl)-2-pyrrolidinylacetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamideN-[1-({4-[2-((1R)-1-aminopropyl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylamino)carboxamideN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(2,2,2-trifluoro-isopropoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl]carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)carboxamide((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]propyl)-2-azetidinylacetamideN-{1-[(4-{2-[(1R)-1-(2-oxopyrrolidinyl)ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[2-(hydroxyethyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-azetidinylacetamide((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxycarboxamideN-[1-({4-[2-((2R)-1-acetylpyrrolidin-2-yl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamidemethyl (2R)-2-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}pyrrolidinecarboxylateN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]propyl)-2-(dimethylamino)acetamideN-((1R)-3-carbamoyl-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)-N-methylacetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxy-N-methylcarboxamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl 2-(dimethylamino)acetateN-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[4-((1S)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl (2S)-2-amino-3-methylbutanoateN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamideN-{1-[(4-{2-[(1R)-1-(2-oxo(1,3-oxazolidin-3-yl))ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxy-N-methylcarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-(phenylmethoxy)propyl)methoxycarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)-N-methylacetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)ethoxy-N-methylcarboxamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamideN-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamideN-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamideN-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamideN-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamideN-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]carboxamideN-{(1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-[(4-bromophenyl)methyl]ethyl}[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-{[4-(2-bromoacetyl)phenyl]methyl}ethyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1S)-1-{[4-(2-bromoacetyl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-carbamoylethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamide(3R)-3-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-3-(acetylamino)propanoicacidN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)isoxazol-5-ylcarboxamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-methoxyacetamideN-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-furylcarboxamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamideN-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamideN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamide

In some embodiments, the chemical entity is a prodrug, such as aphosphate or acyl ester, of one of the compounds listed in Table 1, 2,3, 4, 5, or 6. In some embodiments, the chemical entity is chosen from(3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyldihydrogen phosphate; and(3S)-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]butyldihydrogen phosphate.

The chemical entities described herein can be prepared by following theprocedures set forth, for example, in PCT WO 99/13061, U.S. Pat. No.6,420,561 and PCT WO 98/56756, each of which is incorporated herein byreference. The starting materials and other reactants arecommercially-available, e.g., from Aldrich Chemical Company, Milwaukee,Wis., or may be readily prepared by those skilled in the art usingcommonly employed synthetic methodology.

Unless specified otherwise, the terms “solvent”, “inert organic solvent”or “inert solvent” mean a solvent inert under the conditions of thereaction being described in conjunction therewith, including, forexample, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”),dimethylformamide (“DMF”), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions of thepresent invention are inert organic solvents.

In general, esters of carboxylic acids may be prepared by conventionalesterification procedures, for example alkyl esters may be prepared bytreating the required carboxylic acid with the appropriate alkanol,generally under acidic conditions. Likewise, amides may be preparedusing conventional amidation procedures, for example amides may beprepared by treating an activated carboxylic acid with the appropriateamine. Alternatively, a lower-alkyl ester such as a methyl ester of theacid may be treated with an amine to provide the required amide,optionally in presence of trimethylalluminium following the proceduredescribed in Tetrahedron Lett. 48, 4171-4173, (1977). Carboxyl groupsmay be protected as alkyl esters, for example methyl esters, whichesters may be prepared and removed using conventional procedures, oneconvenient method for converting carbomethoxy to carboxyl is to useaqueous lithium hydroxide.

The salts and solvates mentioned herein may as required be produced bymethods conventional in the art. For example, if an inventive compoundis an acid, a desired base addition salt can be prepared by treatment ofthe free acid with an inorganic or organic base, such as an amine(primary, secondary, or tertiary); an alkali metal or alkaline earthmetal hydroxide; or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids such as glycine andarginine; ammonia; primary, secondary, and tertiary amines; such asethylenediamine, and cyclic amines, such as cyclohexylamine, piperidine,morpholine, and piperazine; as well as inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

If a compound is a base, a desired acid addition salt may be prepared byany suitable method known in the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acidor galacturonic acid, alpha-hydroxy acid, such as citric acid ortartaric acid, amino acid, such as aspartic acid or glutamic acid,aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid,such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonicacid, or the like.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can, of course, also beused.

Referring to Reaction Scheme 1, Step 1, to a solution of a compound ofFormula 103 in an inert solvent such as dichloromethane are added anexcess (such as about 1.2 equivalents) of pentafluorotrifluoroacetateand a base such as triethylamine at about 0° C. The reaction mixture isstirred for about 1 h. The product, a compound of Formula 105, isisolated and purified.

Referring to Reaction Scheme 1, Step 2, to a solution of a compound ofFormula 105 in a polar, aprotic solvent are added an excess (such asabout 1.2 equivalents) of a compound of formulaR₇(CO)—CH(NHR₂)—CH(R₅)(R₆) and a base such as N,N-diisopropylethylamine.The reaction is monitored by, for example, LC/MS, to yield a compound ofFormula 107 wherein R₇ is NH₂, which is isolated and optionallypurified.

Referring to Reaction Scheme 2, to a solution of a compound of Formula201 in a polar, aprotic solvent such as DMF are added an excess (such asabout 1.2 equivalents) of a compound of Formula 105 and a base such asdiisopropylethylamine at room temperature. The reaction mixture ismonitored by, for example, LC/MS. After completion, a primary orsecondary amine in an inert solvent such as THF and HBTU is added to thereaction solution. The reaction mixture is stirred for about 2 days. Theproduct, a compound of Formula 203 wherein R₇ is optionally substitutedamino, is isolated and purified.

In certain embodiments, R₆ in a compound of Formula 203 is a halide,alkyl halide, or aryl halide. This halide can be converted to variousother substituents using a variety of reactions using techniques knownin the art and further described in the examples below.

In other embodiments, R₆ in a compound of Formula 203 is an alkyl oraryl amine. Again, the amine moiety can be alkylated, acylated,converted to the sulfonamide, and the like using techniques known in theart and further described below.

In yet other embodiments, R₆ in a compound of Formula 203 is an alkylalcohol or an aryl alcohol. The hydroxy moiety can be converted to thecorresponding ether or ester using techniques known in the art.

Referring to Reaction Scheme 3, to a solution of a compound of Formula301 in a polar, aprotic solvent such as DMF is added glycinamidehydrochloride, a base such as diisopropylethylamine, and HBTU. Thereaction mixture is stirred for about 15 hours. The product, a compoundof Formula 303, is isolated and purified.

Referring to Reaction Scheme 4, Step 1, to a stirred solution of acompound of Formula 401 wherein n is 0, 1, or 2 in an inert solvent suchas THF at about 0° C. is added an excess (such as about 2 equivalents)of LAH (such as a 1.0 M solution in THF). After stirring for about 2hours, the product, a compound of Formula 403, is isolated and usedwithout further purification.

Referring to Reaction Scheme 4, Step 2, the hydroxy group is convertedto a protected amino group. If the protecting group is phthamide, it canbe made as follows. To a stirred solution of a compound of Formula 403in an inert solvent such as THF are added an excess (such as about 1.1equivalents) of isoindole-1,3-dione and triphenylphosphine. An excess(such as about 1.1 equivalents) of DEAD is then added dropwise and thereaction is stirred for about 30 min. The product, a compound of Formula405, is isolated and purified.

Referring to Reaction Scheme 4, Step 3, the Boc protecting group is thenremoved to form the corresponding free amine. One of skill in the artwill appreciate that this should be accomplished in such a manner as toleave the other protected amine intact. For example, to a solution of acompound of Formula 405 in a nonpolar, aprotic solvent such asdichloromethane is added an acid, such as TFA, at room temperature. Thereaction mixture is stirred for about 20 min. The product, a compound ofFormula 407, is isolated and used without further purification.

Referring to Reaction Scheme 4, Step 4, to a solution of a compound ofFormula 407 in an inert solvent such as DMF are added a compound ofFormula 105 and a base such as diisopropylethylamine at roomtemperature. The reaction mixture is stirred overnight. The product, acompound of Formula 409, is isolated and purified.

Referring to Reaction Scheme 4, Step 5, the amine protecting group, PG,is then removed. If the amine protecting group, PG, is a phthalimide, itcan be removed is follows. To a solution of a compound of Formula 409 ina polar, protic solvent such as methanol is added an excess (such asabout 10 equivalents) of hydrazine hydrate. The reaction mixture isstirred at about 50° C. for about 5 h, and then cooled to roomtemperature. The product, a compound of Formula 411, is isolated andoptionally, purified. Conditions for removing other protecting groupsare known to those of skill in the art.

The free amine of a compound of Formula 411 can be acylated, alkylated,reductively alkylated, or sulfonylated using techniques known to thoseof skill in the art.

In certain compounds of the invention, a particular stereoconfigurationmay be preferred for the compound of Formula I-XIII. For the sake ofbrevity in the remaining description of the synthesis of compounds ofFormula I-XIII, it should be understood that either single isomer or amixture of isomers can be employed to give the corresponding product.

Particular stereoisomers can be obtained from mixtures using techniquesknown in the art. For example, some embodiments, a free amine of Formula505 is dissolved in an inert organic solvent (such as IPA) and warmed to60° C. In a separate vessel, a resolving agent (such asdibenzoyl-D-tartaric acid) is dissolved, such as in the same warmsolvent, and then quickly added (with agitation) to the warm aminesolution. The reaction mixture is left to crystallize by cooling to roomtemperature over 16 hours under continuing agitation. The desired isomeris isolated and purified in the usual manner.

In some embodiments, an optically active amine of Formula 507 can beprepared from the corresponding aryl aldehyde as shown in ReactionScheme 5.

Referring to Reaction Scheme 5, Step 1, a solution of a compound ofFormula 501 and an excess of ammonium acetate in nitroethane is heatedto about reflux for about 8 hours. The product, a compound of Formula503, is isolated and optionally purified.

Referring to Reaction Scheme 5, Step 2, to an about 0° C. solution of areducing agent such as sodium borohydride in an inert solvent such astetrahydrofuran is added an excess (such as about 1.2 equivalents) ofborane-tetrahydrofuran complex. The resulting solution is stirred atroom temperature for about 15 minutes. A compound of Formula 503 in aninert solvent such as tetrahydrofuran is added dropwise, and theresulting solution is refluxed for about 4 hours. The product, acompound of Formula 505, is isolated and optionally purified.

The amine of Formula 505 can be then resolved using techniques known inthe art. For example, a 0° C. solution of the amine of Formula 505 in aninert solvent such as ethyl acetate is saturated with hydrochloric acid(gas). The resulting salt is collected by filtration and dried in vacuo.L-N-Acetylleucine sodium salt is added slowly to a stirred solution ofthe aforementioned salt in water. Crystals form overnight and areremoved by filtration, washed with a small amount of cold water, andrecrystallized from absolute methanol. The crystalline salt of Formula507a is isolated and optionally purified.

The mother liquors, which were rich in a compound of Formula 507b, arecombined, made strongly alkaline, and washed three times with diethylether. The combined organic layers are washed with water and dried oversodium sulfate. Hydrochloric acid is passed through the solution untilthe precipitation of hydrochloride salt is complete. The same procedureas above can be applied with D-N-acetylleucine salt. The crystallinecompound of Formula 507b is isolated and optionally purified.

Referring to Reaction Scheme 6, Step 1, to a solution of a compound ofFormula 601 in a polar protic solvent such as methanol is added anexcess (such as about 2 equivalents) of SOCl₂. After stirring overnightat ambient temperature, the product, a compound of Formula 603, isisolated and used without further purification.

Referring to Reaction Scheme 6, Step 2, to a solution of a compound ofFormula 603 in a polar, protic solvent such as ethanol is added anexcess (such as about 5 equivalents) of N₂H₄.H₂O. The reaction mixtureis heated to reflux and stirred for about 3 h. Upon cooling, theproduct, a compound of Formula 605, is isolated and purified.

Referring to Reaction Scheme 6, Step 3, to a solution of a compound ofFormula 605 in an inert solvent such as THF is added an excess (such asabout 1.1 equivalents) of carbonyldiimidazole. The reaction mixture isheated to reflux and stirred for 1.5 h. Upon cooling, the product, acompound of Formula 607, is isolated and purified.

Referring to Reaction Scheme 6, Step. 4, to a solution of a compound ofFormula 607 in an inert solvent such as acetonitrile is added an excess(such as about 1.1 equivalents) of R₅R₆CH-Z wherein Z is a leaving groupand a base such as K₂CO₃. The reaction mixture is heated to about 80° C.under microwave irradiation for about 30 min followed by filtration andconcentration in vacuo. The product, a compound of Formula 609, isisolated and optionally purified.

Referring to Reaction Scheme 6, Step 5, to a compound of Formula 609 isadded an excess of a primary amine in an inert solvent such as THF. Thereaction mixture is heated to about about 100° C. under microwaveirradiation for about 4 h. The product, a compound of Formula 611, isisolated and purified.

Referring to Reaction Scheme 7, Step 1, a suspension of zinc powder in adry degassed polar, aprotic solvent such as DMF was activated usingtechniques known in the art and further described in the example asfollows. 1,2-Dibromoethane was added to the zinc solution undernitrogen. The mixture was heated using a heat gun for about 30 secondsuntil gas starts to evolve from the solution, indicating the activationof the zinc. The mixture was then allowed to cool to room temperaturefollowed by the addition of TMSCl, and allowed to stir at roomtemperature for 30 min. A solution of a compound of Formula 701 in a drydegassed polar, aprotic solvent such as DMF was added to the zincsolution, and the reaction mixture was stirred for 1 hour at roomtemperature. The solution of 702 is used for the next step.

Referring to Reaction Scheme 7, Step 2, to a solution of 702 was added asolution of a compound of Formula 703 (where X₁ is Br or I) in a drydegassed polar, aprotic solvent such as DMF, and a palladium catalystand a ligand such as Pd₂(dba₃), and tri-o-tolylphospine. The reactionmixture was stirred for 3 hours. The product, a compound of Formula 704is isolated and purified.

Once made, the chemical entities of the invention find use in a varietyof applications involving alteration of mitosis. As will be appreciatedby those skilled in the art, mitosis may be altered in a variety ofways; that is, one can affect mitosis either by increasing or decreasingthe activity of a component in the mitotic pathway. Stated differently,mitosis may be affected (e.g., disrupted) by disturbing equilibrium,either by inhibiting or activating certain components. Similarapproaches may be used to alter meiosis.

In some embodiments, the chemical entities of the invention are used toinhibit mitotic spindle formation, thus causing prolonged cell cyclearrest in mitosis. By “inhibit” in this context is meant decreasing orinterfering with mitotic spindle formation or causing mitotic spindledysfunction. By “mitotic spindle formation” herein is meant organizationof microtubules into bipolar structures by mitotic kinesins. By “mitoticspindle dysfunction” herein is meant mitotic arrest.

The chemical entities of the invention bind to, and/or inhibit theactivity of, one or more mitotic kinesin. In some embodiments, themitotic kinesin is human, although the chemical entities may be used tobind to or inhibit the activity of mitotic kinesins from otherorganisms. In this context, “inhibit” means either increasing ordecreasing spindle pole separation, causing malformation, i.e.,splaying, of mitotic spindle poles, or otherwise causing morphologicalperturbation of the mitotic spindle. Also included within the definitionof a mitotic kinein for these purposes are variants and/or fragments ofsuch protein and more particularly, the motor domain of such protein.

The chemical entities of the invention are used to treat cellularproliferation diseases. Such disease states which can be treated by thechemical entities provided herein include, but are not limited to,cancer (further discussed below), autoimmune disease, fungal disorders,arthritis, graft rejection, inflammatory bowel disease, cellularproliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. Treatment includesinhibiting cellular proliferation. It is appreciated that in some casesthe cells may not be in an abnormal state and still require treatment.Thus, in some embodiments, the invention herein includes application tocells or individuals afflicted or subject to impending affliction withany one of these disorders or states.

The chemical entities, pharmaceutical formulations and methods providedherein are particularly deemed useful for the treatment of cancerincluding solid tumors such as skin, breast, brain, cervical carcinomas,testicular carcinomas, etc. More particularly, cancers that can betreated include, but are not limited to:

-   -   Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,        liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;    -   Lung: bronchogenic carcinoma (squamous cell, undifferentiated        small cell, undifferentiated large cell, adenocarcinoma),        alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma,        lymphoma, chondromatous hamartoma, mesothelioma;    -   Gastrointestinal: esophagus (squamous cell carcinoma,        adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma,        lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,        insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma),        small bowel (adenocarcinoma, lymphoma, carcinoid tumors,        Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,        fibroma), large bowel (adenocarcinoma, tubular adenoma, villous        adenoma, hamartoma, leiomyoma);    -   Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor        [nephroblastoma], lymphoma, leukemia), bladder and urethra        (squamous cell carcinoma, transitional cell carcinoma,        adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis        (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,        choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,        fibroadenoma, adenomatoid tumors, lipoma);    -   Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,        hepatoblastoma, angiosarcoma, hepatocellular adenoma,        hemangioma;    -   Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant        fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant        lymphoma (reticulum cell sarcoma), multiple myeloma, malignant        giant cell tumor chordoma, osteochronfroma (osteocartilaginous        exostoses), benign chondroma, chondroblastoma,        chondromyxofibroma, osteoid osteoma and giant cell tumors;    -   Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,        osteitis deformans), meninges (meningioma, meningiosarcoma,        gliomatosis), brain (astrocytoma, medulloblastoma, glioma,        ependymoma, germinoma [pinealoma], glioblastoma multiform,        oligodendroglioma, schwannoma, retinoblastoma, congenital        tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);    -   Gynecological: uterus (endometrial carcinoma), cervix (cervical        carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian        carcinoma [serous cystadenocarcinoma, mucinous        cystadenocarcinoma, unclassified carcinoma], granulosa-thecal        cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant        teratoma), vulva (squamous cell carcinoma, intraepithelial        carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina        (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma        (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma);    -   Hematologic: blood (myeloid leukemia [acute and chronic], acute        lymphoblastic leukemia, chronic lymphocytic leukemia,        myeloproliferative diseases, multiple myeloma, myelodysplastic        syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant        lymphoma];    -   Skin: malignant melanoma, basal cell carcinoma, squamous cell        carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,        angioma, dermatofibroma, keloids, psoriasis; and    -   Adrenal glands: neuroblastoma.        As used herein, treatment of cancer includes treatment of        cancerous cells, including cells afflicted by any one of the        above-identified conditions. Thus, the term “cancerous cell” as        provided herein, includes a cell afflicted by any one of the        above identified conditions.

Another useful aspect of the invention is a kit having at least onechemical entity described herein and a package insert or other labelingincluding directions treating a cellular proliferative disease byadministering an effective amount of the at least one chemical entity.The chemical entity in the kits of the invention is particularlyprovided as one or more doses for a course of treatment for a cellularproliferative disease, each dose being a pharmaceutical formulationincluding a pharmaceutical excipient and at least one chemical entitydescribed herein.

For assay of mitotic kinesin-modulating activity, generally either amitotic kinesin or at least one chemical entity described herein isnon-diffusably bound to an insoluble support having isolated samplereceiving areas (e.g., a microtiter plate, an array, etc.). Theinsoluble support may be made of any composition to which the sample canbe bound, is readily separated from soluble material, and is otherwisecompatible with the overall method of screening. The surface of suchsupports may be solid or porous and of any convenient shape. Examples ofsuitable insoluble supports include microtiter plates, arrays, membranesand beads. These are typically made of glass, plastic (e.g.,polystyrene), polysaccharides, nylon or nitrocellulose, Teflon™, etc.Microtiter plates and arrays are especially convenient because a largenumber of assays can be carried out simultaneously, using small amountsof reagents and samples. The particular manner of binding of the sampleis not crucial so long as it is compatible with the reagents and overallmethods of the invention, maintains the activity of the sample and isnondiffusable. Particular methods of binding include the use ofantibodies (which do not sterically block either the ligand binding siteor activation sequence when the protein is bound to-the support), directbinding to “sticky” or ionic supports, chemical crosslinking, thesynthesis of the protein or agent on the surface, etc. Following bindingof the sample, excess unbound material is removed by washing. The samplereceiving areas may then be blocked through incubation with bovine serumalbumin (BSA), casein or other innocuous protein or other moiety.

The chemical entities of the invention may be used on their own toinhibit the activity of a mitotic kinesin. In some embodiments, at leastone chemical entity of the invention is combined with a mitotic kinesinand the activity of the mitotic kinesin is assayed. Kinesin activity isknown in the art and includes one or more of the following: the abilityto affect ATP hydrolysis; microtubule binding; gliding andpolymerization/depolymerization (effects on microtubule dynamics);binding to other proteins of the spindle; binding to proteins involvedin cell-cycle control; serving as a substrate to other enzymes, such askinases or proteases; and specific kinesin cellular activities such asspindle pole separation.

Methods of performing motility assays are well known to those of skillin the art. (See e.g., Hall, et al. (1996), Biophys. J., 71: 3467-3476,Turner et al., 1996, AnaL Biochem. 242 (1):20-5; Gittes et al., 1996,Biophys. J. 70(1): 418-29;Shirakawa et al., 1995, J. Exp. BioL 198:1809-15; Winkelmann et al., 1995, Biophys. J. 68: 2444-53; Winkelmann etal., 1995, Biophys. J. 68: 72S.)

Methods known in the art for determining ATPase hydrolysis activity alsocan be used. Suitably, solution based assays are utilized. U.S. Pat. No.6,410,254, hereby incorporated by reference in its entirety, describessuch assays. Alternatively, conventional methods are used. For example,P_(i) release from kinesin (and more particularly, the motor domain of amitotic kinesin) can be quantified. In some embodiments, the ATPasehydrolysis activity assay utilizes 0.3 M PCA (perchloric acid) andmalachite green reagent (8.27 mM sodium molybdate II, 0.33 mM malachitegreen oxalate, and 0.8 mM Triton X-1 00). To perform the assay, 10 μL ofthe reaction mixture is quenched in 90 μL of cold 0.3 M PCA. Phosphatestandards are used so data can be converted to mM inorganic phosphatereleased. When all reactions and standards have been quenched in PCA,100 μL of malachite green reagent is added to the relevant wells ine.g., a microtiter plate. The mixture is developed for 10-15 minutes andthe plate is read at an absorbance of 650 nm. If phosphate standardswere used, absorbance readings can be converted to mM P_(i) and plottedover time. Additionally, ATPase assays known in the art include theluciferase assay.

ATPase activity of kinesin motor domains also can be used to monitor theeffects of agents and are well known to those skilled in the art. Insome embodiments ATPase assays of kinesin are performed in the absenceof microtubules. In some embodiments, the ATPase assays are performed inthe presence of microtubules. Different types of agents can be detectedin the above assays. In some embodiments, the effect of an agent isindependent of the concentration of microtubules and ATP. In someembodiments, the effect of the agents on kinesin ATPase can be decreasedby increasing the concentrations of ATP, microtubules or both. In someembodiments, the effect of the agent is increased by increasingconcentrations of ATP, microtubules or both.

Chemical entities that inhibit the biochemical activity of a mitotickinesin in vitro may then be screened in vivo. In vivo screening methodsinclude assays of cell cycle distribution, cell viability, or thepresence, morphology, activity, distribution, or number of mitoticspindles. Methods for monitoring cell cycle distribution of a cellpopulation, for example, by flow cytometry, are well known to thoseskilled in the art, as are methods for determining cell viability. Seefor example, U.S. Pat. No. 6,437,115, hereby incorporated by referencein its entirety. Microscopic methods for monitoring spindle formationand malformation are well known to those of skill in the art (see, e.g.,Whitehead and Rattner (1998), J. Cell Sci. 111:2551-61; Galgio et al,(199,6) J. Cell Biol., 135:399-414), each incorporated herein byreference in its entirety.

The chemical entities of the invention inhibit one or more mitotickinesins. One measure of inhibition is IC₅₀, defined as theconcentration of the chemical entity at which the activity of themitotic kinesin is decreased by fifty percent relative to a control. Insome embodiments, the at least one chemical entity has an IC₅₀ of lessthan about 1 mM. In some embodiments, the at least one chemical entityhas an IC₅₀ of less than about 100 μM. In some embodiments, the at leastone chemical entity has an IC₅₀ of less than about 10 μM. In someembodiments, the at least one chemical entity has an IC₅₀ of less thanabout 1 μM. In some embodiments, the at least one chemical entity has anIC₅₀ of less than about 100 nM. In some embodiments, the at least onechemical entity has an IC₅₀ of less than about 10 nM. Measurement ofIC₅₀ is done using an ATPase assay such as described herein.

Another measure of inhibition is K_(i). For chemical entities withIC₅₀'s less than 1 μM, the K_(i) or K_(d) is defined as the dissociationrate constant for the interaction of the compounds described herein witha mitotic kinesin. In some embodiments, the at least one chemical entityhas a K_(i) of less than about 100 μM. In some embodiments, the at leastone chemical entity has a K_(i) of less than about 10 μM. In someembodiments, the at least one chemical entity has a K_(i) of less thanabout 1 μM. In some embodiments, the at least one chemical entity has aK_(i) of less than about 100 nM. In some embodiments, the at least onechemical entity has a K_(i) of less than about 10 nM.

The K_(i) for a chemical entity is determined from the IC₅₀ based onthree assumptions and the Michaelis-Menten equation. First, only onecompound molecule binds to the enzyme and there is no cooperativity.Second, the concentrations of active enzyme and the compound tested areknown (i.e., there are no significant amounts of impurities or inactiveforms in the preparations). Third, the enzymatic rate of theenzyme-inhibitor complex is zero. The rate (i.e., compoundconcentration) data are fitted to the equation:$V = {V_{\max}{E_{0}\left\lbrack {I - \frac{\left( {E_{0} + I_{0} + {Kd}} \right) - \sqrt{\left( {E_{0} + I_{0} + {Kd}} \right)^{2} - {4E_{0}I_{0}}}}{2E_{0}}} \right\rbrack}}$where V is the observed rate, V_(max) is the rate of the free enzyme, I₀is the inhibitor concentration, E₀ is the enzyme concentration, andK_(d) is the dissociation constant of the enzyme-inhibitor complex.

Another measure of inhibition is GI₅₀, defined as the concentration ofthe chemical entity that results in a decrease in the rate of cellgrowth by fifty percent. In some embodiments, the at least one chemicalentity has a GI₅₀ of less than about 1 mM. In some embodiments, the atleast one chemical entity has a GI₅₀ of less than about 20 μM. In someembodiments, the at least one chemical entity has a GI₅₀ of less thanabout 10 μM. In some embodiments, the at least one chemical entity has aGI₅₀ of less than about 1 μM. In some embodiments, the at least onechemical entity has a GI₅₀ of less than about 100 nM. In someembodiments, the at least one chemical entity has a GI₅₀ of less thanabout 10 nM. Measurement of GI₅₀ is done using a cell proliferationassay such as described herein. Chemical entities of this class werefound to inhibit cell proliferation.

In vitro potency of small molecule inhibitors is determined, forexample, by assaying human ovarian cancer cells (SKOV3) for viabilityfollowing a 72-hour exposure to a 9-point dilution series of compound.Cell viability is determined by measuring the absorbance of formazon, aproduct formed by the bioreduction of MTS/PMS, a commercially availablereagent. Each point on the dose-response curve is calculated as apercent of untreated control cells at 72 hours minus backgroundabsorption (complete cell kill).

Anti-proliferative compounds that have been successfully applied in theclinic to treatment of cancer (cancer chemotherapeutics) have GI₅₀'sthat vary greatly. For example, in A549 cells, paclitaxel GI₅₀ is 4 nM,doxorubicin is 63 nM, 5-fluorouracil is 1 μM, and hydroxyurea is 500 μM(data provided by National Cancer Institute, Developmental TherapeuticProgram, http://dtp.nci.nih.gov/). Therefore, compounds that inhibitcellular proliferation, irrespective of the concentration demonstratinginhibition, have potential clinical usefulness.

To employ the chemical entities of the invention in a method ofscreening for compounds that bind to a mitotic kinesin, the mitotickinesin is bound to a support, and a compound of the invention is addedto the assay. Alternatively, the chemical entity of the invention isbound to the support and a mitotic kinesin is added. Classes ofcompounds among which novel binding agents may be sought includespecific antibodies, non-natural binding agents identified in screens ofchemical libraries, peptide analogs, etc. Of particular interest arescreening assays for candidate agents that have a low toxicity for humancells. A wide variety of assays may be used for this purpose, includinglabeled in vitro protein-protein binding assays, electrophoreticmobility shift assays, immunoassays for protein binding, functionalassays (phosphorylation assays, etc.) and the like.

The determination of the binding of the chemical entities of theinvention to a mitotic kinesin may be done in a number of ways. In someembodiments, the chemical entity is labeled, for example, with afluorescent or radioactive moiety, and binding is determined directly.For example, this may be done by attaching all or a portion of a mitotickinesin to a solid support, adding a labeled test compound (for examplea chemical entity of the invention in which at least one atom has beenreplaced by a detectable isotope), washing off excess reagent, anddetermining whether the amount of the label is that present on the solidsupport.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In some embodiments, only one of the components is labeled. For example,the kinesin proteins may be labeled at tyrosine positions using ¹²⁵I, orwith fluorophores. Alternatively, more than one component may be labeledwith different labels; using ¹²⁵I for the proteins, for example, and afluorophor for the antimitotic agents.

The chemical entities of the invention may also be used as competitorsto screen for additional drug candidates. “Candidate agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. Screens of this sort may be performedeither in the presence or absence of microtubules. In the case whereprotein binding or activity is screened, particular embodiments excludemolecules already known to bind to that particular protein, for example,polymer structures such as microtubules, and energy sources such as ATP.Particular embodiments of assays herein include candidate agents whichdo not bind the cellular proliferation protein in its endogenous nativestate termed herein as “exogenous” agents. In some embodiments,exogenous agents further exclude antibodies to the mitotic kinesin.

Candidate agents can encompass numerous chemical classes, thoughtypically they are small organic compounds having a molecular weight ofmore than 100 and less than about 2,500 daltons. Candidate agentscomprise functional groups necessary for structural interaction withproteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl-, hydroxy-, ether, orcarboxyl group, generally at least two of the functional chemicalgroups. The candidate agents often comprise cyclical carbon orheterocyclic structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Candidateagents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs or combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, and/or amidification to producestructural analogs.

Competitive screening assays may be done by combining a mitotic kinesinand a drug candidate in a first sample. A second sample comprises atleast one chemical entity of the present invention, a mitotic kinesinand a drug candidate. This may be performed in either the presence orabsence of microtubules. The binding of the drug candidate is determinedfor both samples, and a change, or difference in binding between the twosamples indicates the presence of a drug candidate capable of binding toa mitotic kinesin and potentially inhibiting its activity. That is, ifthe binding of the drug candidate is different in the second samplerelative to the first sample, the drug candidate is capable of bindingto a mitotic kinesin.

In some embodiments, the binding of the candidate agent to a mitotickinesin is determined through the use of competitive binding assays. Insome embodiments, the competitor is a binding moiety known to bind tothe mitotic kinesin, such as an antibody, peptide, binding partner,ligand, etc. Under certain circumstances, there may be competitivebinding as between the candidate agent and the binding moiety, with thebinding moiety displacing the candidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to themitotic kinesin for a time sufficient to allow binding, if present.Incubations may be performed at any temperature which facilitatesoptimal activity, typically between 4 and 40° C.

Incubation periods are selected for optimum activity, but may also beoptimized to facilitate rapid high throughput screening. Typicallybetween 0.1 and 1 hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In some embodiments, the competitor is added first, followed by thecandidate agent. Displacement of the competitor is an indication thecandidate agent is binding to the mitotic kinesin and thus is capable ofbinding to, and potentially inhibiting, the activity of the mitotickinesin. In some embodiments, either component can be labeled. Thus, forexample, if the competitor is labeled, the presence of label in the washsolution indicates displacement by the agent. Alternatively, if thecandidate agent is labeled, the presence of the label on the supportindicates displacement.

In some embodiments, the candidate agent is added first, with incubationand washing, followed by the competitor. The absence of binding by thecompetitor may indicate the candidate agent is bound to the mitotickinesin with a higher affinity. Thus, if the candidate agent is labeled,the presence of the label on the support, coupled with a lack ofcompetitor binding, may indicate the candidate agent is capable ofbinding to the mitotic kinesin.

Inhibition is tested by screening for candidate agents capable ofinhibiting the activity of a mitotic kinesin comprising the steps ofcombining a candidate agent with a mitotic kinesin as above, anddetermining an alteration in the biological activity of the mitotickinesin. Thus, in some embodiments, the candidate agent should both bindto the mitotic kinesin (although this may not be necessary), and alterits biological or biochemical activity as defined herein. The methodsinclude both in vitro screening methods and in vivo screening of cellsfor alterations in cell cycle distribution, cell viability, or for thepresence, morpohology, activity, distribution, or amount of mitoticspindles, as are generally outlined above.

Alternatively, differential screening may be used to identify drugcandidates that bind to the native mitotic kinesin but cannot bind to amodified mitotic kinesin.

Positive controls and negative controls may be used in the assays.Suitably all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofall samples is for a time sufficient for the binding of the agent to theprotein. Following incubation, all samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples may be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents may be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which may be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,may be used. The mixture of components may be added in any order thatprovides for the requisite binding.

Accordingly, the chemical entities of the invention are administered tocells. By “administered” herein is meant administration of atherapeutically effective dose of at least one chemical entity of theinvention to a cell either in cell culture or in a patient. By“therapeutically effective dose” herein is meant a dose that producesthe effects for which it is administered. The exact dose will depend onthe purpose of the treatment, and will be ascertainable by one skilledin the art using known techniques. As is known in the art, adjustmentsfor systemic versus localized delivery, age, body weight, generalhealth, sex, diet, time of administration, drug interaction and theseverity of the condition may be necessary, and will be ascertainablewith routine experimentation by those skilled in the art. By “cells”herein is meant any cell in which mitosis or meiosis can be altered.

A “patient” for the purposes of the present invention includes bothhumans and other animals, particularly mammals, and other organisms.Thus the methods are applicable to both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal, and moreparticularly, the patient is human.

Chemical entities of the invention having the desired pharmacologicalactivity may be administered, in some embodiments, as a pharmaceuticallyacceptable composition comprising an pharmaceutical excipient, to apatient, as described herein. Depending upon the manner of introduction,the chemical entities may be formulated in a variety of ways asdiscussed below. The concentration of the at least one chemical entityin the formulation may vary from about 0.1-100 wt. %.

The agents may be administered alone or in combination with othertreatments, i.e., radiation, or other chemotherapeutic agents such asthe taxane class of agents that appear to act on microtubule formationor the camptothecin class of topoisomerase I inhibitors. When used,other chemotherapeutic agents may be administered before, concurrently,or after administration of at least one chemical entity of the presentinvention. In one aspect of the invention, at least one chemical entityof the present invention is co-administered with one or more otherchemotherapeutic agents. By “co-administer” it is meant that the atleast one chemical entity is administered to a patient such that the atleast one chemical entity as well as the co-administered compound may befound in the patient's bloodstream at the same time, regardless when thecompounds are actually administered, including simultaneously.

The administration of the chemical entities of the present invention canbe done in a variety of ways, including, but not limited to, orally,subcutaneously, intravenously, intranasally, transdermally,intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally,or intraocularly. In some instances, for example, in the treatment ofwounds and inflammation, the compound or composition may be directlyapplied as a solution or spray.

Pharmaceutical dosage forms include at least one chemical entitydescribed herein and one or more pharmaceutical excipients. As is knownin the art, pharmaceutical excipients are secondary ingredients whichfunction to enable or enhance the delivery of a drug or medicine in avariety of dosage forms (e.g.: oral forms such as tablets, capsules, andliquids; topical forms such as dermal, opthalmic, and otic forms;suppositories; injectables; respiratory forms and the like).Pharmaceutical excipients include inert or inactive ingredients,synergists or chemicals that substantively contribute to the medicinaleffects of the active ingredient. For example, pharmaceutical excipientsmay function to improve flow characteristics, product uniformity,stability, taste, or appearance, to ease handling and administration ofdose, for convenience of use, or to control bioavailability. Whilepharmaceutical excipients are commonly described as being inert orinactive, it is appreciated in the art that there is a relationshipbetween the properties of the pharmaceutical excipients and the dosageforms containing them.

Pharmaceutical excipients suitable for use as carriers or diluents arewell known in the art, and may be used in a variety of formulations.See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R.Gennaro, Editor, Mack Publishing Company (1990); Remington: The Scienceand Practice of Pharmacy, 20th Edition, A. R. Gennaro, Editor,Lippincott Williams & Wilkins (2000); Handbook of PharmaceuticalExcipients, 3rd Edition, A. H. Kibbe, Editor, American PharmaceuticalAssociation, and Pharmaceutical Press (2000); and Handbook ofPharmaceutical Additives, compiled by Michael and Irene Ash, Gower(1995), each of which is incorporated herein by reference for allpurposes.

Oral solid dosage forms such as tablets will typically comprise one ormore pharmaceutical excipients, which may for example help impartsatisfactory processing and compression characteristics, or provideadditional desirable physical characteristics to the tablet. Suchpharmaceutical excipients may be selected from diluents, binders,glidants, lubricants, disintegrants, colors, flavors, sweetening agents,polymers, waxes or other solubility-retarding materials.

Compositions for intravenous administration will generally compriseintravenous fluids, i.e., sterile solutions of simple chemicals such assugars, amino acids or electrolytes, which can be easily carried by thecirculatory system and assimilated. Such fluids are prepared with waterfor injection USP.

Dosage forms for parenteral administration will generally comprisefluids, particularly intravenous fluids, i.e., sterile solutions ofsimple chemicals such as sugars, amino acids or electrolytes, which canbe easily carried by the circulatory system and assimilated. Such fluidsare typically prepared with water for injection USP. Fluids usedcommonly for intravenous (IV) use are disclosed in Remington, TheScience and Practice of Pharmacy [full citation previously provided],and include:

-   -   alcohol, e.g., 5% alcohol (e.g., in dextrose and water (“D/W”)        or D/W in normal saline solution (“NSS”), including in 5%        dextrose and water (“D5/W”), or D5/W in NSS);    -   synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g.,        3.5 or 7; 8.5; 3.5, 5.5 or 8.5 % respectively;    -   ammonium chloride e.g., 2.14%;    -   dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%;    -   dextran 70, in NSS e.g., 6% or in D5/W e.g., 6%;    -   dextrose (glucose, D5/W) e.g., 2.5-50%;    -   dextrose and sodium chloride e.g., 5-20% dextrose and 0.22-0.9%        NaCl;    -   lactated Ringer's (Hartmann's) e.g., NaCl 0.6%, KCl 0.03%, CaCl₂        0.02%;    -   lactate 0.3%;    -   mannitol e.g., 5%, optionally in combination with dextrose e.g.,        10% or NaCl e.g., 15 or 20%;    -   multiple electrolyte solutions with varying combinations of        electrolytes, dextrose, fructose, invert sugar Ringer's e.g.,        NaCl 0.86%, KCl 0.03%, CaCl₂ 0.033%;    -   sodium bicarbonate e.g., 5%;    -   sodium chloride e.g., 0.45, 0.9, 3, or 5%;    -   sodium lactate e.g., ⅙ M; and    -   sterile water for injection        The pH of such IV fluids may vary, and will typically be from        3.5 to 8 as known in the art.

The chemical entityies of the invention can be administered alone or incombination with other treatments, i.e., radiation, or other therapeuticagents, such as the taxane class of agents that appear to act onmicrotubule formation or the camptothecin class of topoisomerase Iinhibitors. When so-used, other therapeutic agents can be administeredbefore, concurrently (whether in separate dosage forms or in a combineddosage form), or after administration of an active agent of the presentinvention.

The following examples serve to more fully describe the manner of usingthe above-described invention. It is understood that these examples inno way serve to limit the true scope of this invention, but rather arepresented for illustrative purposes. All publications, including but notlimited to patents and patent applications, cited in this specificationare herein incorporated by reference as if each individual publicationwere specifically and individually indicated to be incorporated byreference herein as though fully set forth.

EXAMPLES

To a solution of 4-isopropoxylbenzoic acid 1 (25 g, 140 mmol) in DMF(150 mL) was added NCS (24 g, 182 mmol). The reaction mixture wasstirred overnight. H₂O (500 mL) was added to the reaction mixture. T,and the precipitate was collected, and washed with water, and dried invacuo to give 2 (26.4 g, 88%) as a white solid, which was used in thenext step without further purification. LRMS (M+H⁺) m/z 213.0.

To a solution of 2 (20 g, 93 mmol) in dichloromethane were addedpentafluorophenyltrifluoroacetate (20 mL, 112 mmol) and triethylamine(17 mL, 112 mmol) at 0° C. The reaction mixture was stirred for 1 h. Thesolution was concentrated and the mixture purified by flash columnchromatography (100% DCM) to give 3 (35 g, quant.) as a white solid.

To a solution of 3 in DMF (0.2 M) were added amino acid (1.2 equiv.) andN, N-diisopropylethylamine (3 equiv.). The reaction was monitored byLC/MS. After completion, methylamine (2 M in THF, 1.5 equiv.) and HBTU(1.5 equiv.) were added to the reaction solution. The reaction mixturewas stirred for 4 h. The product was purified by either HPLC or flashcolumn chromatography to give 4.

To a solution of H-Phe(4-Br)—OH (2, 2.5 g, 10 mmol) in DMF (20 mL) wereadded 3 (4.7 g, 12 mmol) and diisopropylethylamine (5.4 mL, 30 mmol) atroom temperature. The reaction mixture was monitored by LC/MS. Aftercompletion, methylamine (2 M in THF, 7.7 mL, 15 mmol) and HBTU (5.8 g,15 mmol) were added to the reaction solution. The reaction mixture wasstirred for 2 days. The mixture was filtered, and the filtrate waspurified by RP-HPLC using a mixture of acetonitrile and H₂O to give 4(2.3 g, 50%). LRMS (M+H⁺) m/z 455.0.

To a suspension of 4 (71 mg, 0.16 mmol) in dioxane (1 mL) were addedpiperazine (16 mg, 0.19 mmol), palladium (II) acetate (4 mg, 0.016mmol), dicyclohexylphosphino-2′-(N,N′-dimethylamino)-biphenyl (6 mg,0.016 mmol), and cesium carbonate (104 mg, 0.32 mmol). The resultingmixture was stirred for 36 hours at 110° C. The reaction mixture wasdiluted with EtOAc. The organic layer was washed with saturated NaHCO₃(20 mL) and brine, dried over Na₂SO₄, and concentrated. The residue waspurified by RP-HPLC using a mixture of acetonitrile and H₂O to give 1a(6 mg, 8%). LRMS (M+H⁺) m/z 459.2.

To a solution of H-Tyr-NH₂ HCl (2, 830 mg, 3.8 mmol) in DMF (5 mL) wereadded 3 (1.8 g, 4.5 mmol) and diisopropylethylamine (3.4 mL, 19 mmol) atroom temperature. The reaction was stirred for 20 hours and filteredafter adding water. The white precipitate was recrystallized indichloromethane and methanol to give 4 as white crystals (1.120 g, 78%).LRMS (M+H⁺) m/z 377.1.

To a solution of 4 (50 mg, 0.13 mmol) in DMF (1 mL) were added(S)-(+)-3-bromo-2-methyl-1-propanol (0.083 mL, 0.8 mmol) and potassiumcarbonate (110 mg, 0.8 mmol). The resulting mixture was stirred for 15hours at 50° C. The mixture was filtered, and the filtrate was purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 1b (30 mg,51%). LRMS (M+H⁺) m/z 449.1.

Example 4

To a solution of H-Tyr-OBut (2, 1.9 g, 8 mmol) in DMF (50 mL) were added3 (2.4 g, 6.2 mmol) and diisopropylethylamine (3.3 mL, 19 mmol) at roomtemperature. The reaction was stirred for 2 hours. The resultingsolution was diluted with EtOAc (200 mL) and washed with saturatedNaHCO₃ (50 mL). The organic layer was separated, washed with brine,dried over Na₂SO₄, and concentrated to give a yellow solid. To asolution of the yellow solid in dichloromethane (10 mL) was addedtrifluoroacetic acid (30 mL). The mixture was stirred at roomtemperature for 12 hours and then concentrated under reduced pressure.The residue was dried in vacuo to give 4 (3.1 g), which was used in thenext step without further purification. LRMS (M−H⁺) m/z 376.1.

To a solution of 4 (3.1 g, 8 mmol) in DMF (25 mL) was added glycinamidehydrochloride (1.1 g, 9.6 mmol), diisopropylethylamine (7 mL, 40 mmol),and HBTU (3.6 g, 9.6 mmol). The reaction mixture was stirred for 15hours, after which solution was diluted with ethyl acetate and washedwith saturated NaHCO₃. The organic layer was separated, washed withbrine, dried over Na₂SO₄, and concentrated. The resulting crude waspurified by RP-HPLC using a mixture of acetonitrile and H₂O to give 5(38 mg, 35%). LRMS (M+H⁺) m/z 434.1.

To a solution of 5 (100 mg, 0.23 mmol) in DMF (1 mL) were addedcyclopropylmethyl bromide (0.18 mL, 1.84 mmol) and potassium carbonate(317 mg, 2.3 mmol). The resulting mixture was stirred for 10 hours at80° C. The mixture was filtered, and the filtrate was purified byRP-HPLC using a mixture of acetonitrile and H₂O to give 1c (36 mg, 34%).LRMS (M+H⁺) m/z 488.1.

Example 5

To a solution of 4 (80 mg, 0.2 mmol) in DMF (1 mL) were added(±)-3-bromo-1-phenyl-2-pyrrolidinone (250 mg, 1 mmol) and potassiumcarbonate (235 mg, 1.7 mmol). The resulting mixture was stirred for 10hours at 110° C. The mixture was filtered, and the filtrate was purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 5 (38 mg,35%). LRMS (M+H⁺) m/z 536.1.

Example 6

To a solution of 4 (70 mg, 0.19 mmol) in DMF (1 mL) were added3-(hydroxymethyl) pyridine (0.023 mL, 0.23 mmol), triphenylphosphine(100 mg, 0.38 mmol), and diisopropylazodicarboxylate (0.055 mL, 0.38mmol). The resulting mixture was stirred for 20 hours at roomtemperature. The reaction solution was concentrated and purified viaflash column chromatography using a mixture of ethyl acetate and hexaneas eluent to give 1f (22 mg, 25%). LRMS (M+H⁺) m/z 468.2.

Example 7

To a solution of 4 (50 mg, 0.12 mmol) in toluene (2 mL) was added2-(fluorophenyl) boronic acid (20 mg, 0.14 mmol),tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.04 mmol), and 2 Msodium carbonate (0.18 mL, 0.36 mmol). The reaction mixture was stirredfor 90 min at 100° C. The resulting solution was purified by RP-HPLCusing a mixture of acetonitrile and H₂O to give 5 (22 mg, 40%). LRMS(M+H⁺) m/z 469.2.

Example 8

To a solution of 4 (45 mg, 0.1 mmol) in DMF (1 mL) were addedbis(pinacolate) diboron (30 mg, 0.12 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (17 mg, 0.02 mmol), and potassium acetate (39mg, 0.4 mmol). The reaction mixture was stirred for 1 hour at 80° C. Theresulting mixture was added 4-bromo-3,5-dimethylisoxazole (35 mg, 0.2mmol) and 2 M sodium carbonate (0.4 mL, 0.8 mmol). The mixture wasstirred at 80° C. for 90 min. The resulting residue was filtered, andthe filtrate was purified by RP-HPLC using a mixture of acetonitrile andH₂O to give 1h (23 mg, 49%). LRMS (M+H⁺) m/z 470.1.

Example 9

To a solution of 4 (62 mg, 0.14 mmol) in DMF (1 mL) was addedbis(pinacolate) diboron (42mg, 0.16 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (34 mg, 0.04 mmol), and potassium acetate (54mg, 0.55 mmol). The reaction mixture was stirred for 1 hour at 80° C.The resulting mixture was added N-methyl-2-bromobenzimidazole (58 mg,0.27 mmol) and 2 M sodium carbonate (0.54 mL, 1.08 mmol). The mixturewas stirred at 80° C. for 60 min. The resulting solution was dilutedwith ethylacetate (20 mL), and washed with saturated NaHCO₃ (20 mL). Theorganic layer was separated, washed with brine, dried over Na₂SO₄, andconcentrated. The resulting residue was purified by RP-HPLC using amixture of acetonitrile and H₂O to give 1i (44 mg, 64%). LRMS (M+H⁺) m/z505.1.

Example 10

To a solution of 4 (50 mg, 0.13 mmol) in DMF (1 mL) were addedbis(pinacolate) diboron (34 mg, 0.13 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (27 mg, 0.03 mmol), and potassium acetate (43mg, 0.44 mmol). The reaction mixture was stirred for 1 hour at 80° C. Tothe resulting mixture was added 3-bromothiophene-2-carbonitrile (41 mg,0.22 mmol) and 2 M sodium carbonate (0.44 mL, 0.88 mmol). The mixturewas stirred at 80° C. for 90 min. The resulting residue was filtered,and the filtrate was purified by RP-HPLC using a mixture of acetonitrileand H₂O to give 5 (20 mg, 37%). LRMS (M+H⁺) m/z 482.1

Example 11

To a solution of 4 (85 mg, 0.2 mmol) in toluene (2 mL) was added1-t-butyl-1,3-dihydro-imidazol-2-one (53 mg, 0.4 mmol), copper(I) iodide(18 mg, 0.1 mmol), trans-1,2-diamino-cyclohexane (11 mg, 0.1 mmol), andcesium carbonate (124 mg, 0.4 mmol). The reaction mixture was stirredfor 4 hours at 100° C. The mixture was filtered, and the filtrate wasconcentrated. The resulting residue was filtered, and the filtrate waspurified by RP-HPLC using a mixture of acetonitrile and H₂O to give 1k(27 mg, 28%). LRMS (M+H⁺) m/z 513.1.

Example 12

To a solution of 4 (100 mg, 0.2 mmol) in dioxane (2 mL) was addedbenzimidazole (39 mg, 0.33 mmol), copper (I) iodide (8.4 mg, 0.04 mmol),1,10-phenanthroline (16 mg, 0.1 mmol), and cesium carbonate (144 mg,0.44 mmol). The reaction mixture was stirred for 15 hours at 100° C. Themixture was filtered, and the filtrate was concentrated. The resultingresidue was filtered, and the filtrate was purified by RP-HPLC using amixture of acetonitrile and H₂O to give 11 (5.7 mg, 6%). LRMS (M+H⁺) m/z491.1.

Example 13

To a solution of 4 (60 mg, 0.16 mmol) in toluene (1 mL) was added2-chlorobenzimidazole (50 mg, 0.32 mmol), copper(I) iodide (9 mg, 0.05),and cesium carbonate (105 mg, 0.32 mmol). The reaction mixture wasstirred for 28 hours at 110° C. The mixture was filtered, and thefiltrate was purified by RP-HPLC using a mixture of acetonitrile and H₂Oto give 1 M (8 mg, 10%). LRMS (M+H⁺) m/z 493.0.

To a solution of 4 (50 mg, 0.1 mmol) in toluene (1 mL) was added phenol(21 mg, 0.2 mmol), copper(I) iodide (6 mg, 0.03 mmol), and cesiumcarbonate (72 mg, 0.2 mmol). The reaction mixture was stirred for 5hours at 115° C. The mixture was filtered, and the filtrate wasconcentrated. The resulting residue was purified via flash columnchromatography using a mixture of ethyl acetate and hexane as eluent togive 1n (23 mg, 45%). LRMS (M+H⁺) m/z 467.1.

To a solution of 1 (2.3 g, 12.6 mmol) in DMF (30 mL) were added 2 (4.0g, 10.5 mmol) and N,N-diisopropylethylamine (5.2 mL, 30 mmol). Thereaction was monitored by LC/MS. The resulting solution was used in thenext step without further purification. LRMS (M+H⁺) m/z 377.1.

To a solution of crude 3 in DMF (6 mL, ˜2 mmol) were added glycinamideHCl (330 mg, 3 mmol), HBTU (1.14 g, 3 mmol) andN,N-diisopropylethylamine (522 μL, 3 mmol). The reaction was stirredovernight. The resulting crude product was purified via RP-HPLC using amixture of acetonitrile and H₂O to give 4 (600 mg, 69% from 2). LRMS(M+H⁺) m/z 433.1.

To a solution of crude 3 in DMF (15 mL, ˜5.25 mmol) were addedmethylamine (2 M in THF, 4 mL, 8 mmol), and HBTU (3 g, 7.9 mmol). Thereaction was stirred overnight. The mixture was diluted with ethylacetate (200 mL). The organic layer was washed with H₂O, brine, driedover sodium sulfate, and concentrated. The resulting crude 5 was used inthe next step without further purification. LRMS (M+H⁺) m/z 390.1.

To a solution of crude 5 (75 mg, ˜0.2 mmol) in dichloromethane (2 mL)were added benzoyl chloride (23 μL, 0.2 mmol) andN,N-diisopropylethylamine (35 μL, 0.2 mmol). The reaction mixture wasstirred overnight. The solution was concentrated and purified by RP-HPLCusing a mixture of acetonitrile and H₂O to give 6 (36 mg, 40% from 2).LRMS (M+H⁺) m/z 494.1

To a solution of 5 (75 mg, ˜0.2 mmol) in dichloromethane (2 mL) wasadded phenyl isocyanate (26 μL, 0.24 mmol). The reaction mixture wasstirred overnight. The resulting solution was concentrated and purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 7 (40 mg, 39%from 2). LRMS (M+H⁺) m/z 509.1.

To a solution of 5 (75 mg, 0.19 mmol) in dichloromethane (3 mL) wereadded isobutyl chloroformate (38 μL, 0.29 mmol) andN,N-diisopropylethylamine (50 μL, 0.29 mmol). The reaction mixture wasstirred overnight. The resulting solution was concentrated and purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 8 (45 mg,48%). LRMS (M+H⁺) m/z 490.1.

To a solution of 5 (75 mg, 0.19 mmol) in dichloromethane (5 mL) wereadded dimethylsulfamoyl chloride (30 μL, 0.29 mmol),N,N-diisopropylethylamine (50 μL, 0.29 mmol) and DMAP (50 mg, 0.4 mmol).The reaction mixture was stirred overnight. The reaction mixture wasthen heated to 30° C. and stirring continued for 8 h. The resultingsolution was concentrated and purified by RP-HPLC using a mixture ofacetonitrile and H₂O to give 9 (30 mg, 32%). LRMS (M+H⁺) m/z 497.1.

To a solution of H-Phe(4-COOtBu)-OH (5.8 g, 22 mmol) in ethyl acetate(60 mL) and water (20 mL) were added platinum (IV) oxide (400 mg, 1.8mmol) and acetic acid (50 mL). The reaction mixture was stirred under astream of H₂ (60 psi) for 20 hrs. The catalyst was removed by filtrationthrough a PTFE (0.45 μm) filter and the solvent evaporated to give 2(5.9 g), which was used in the next step without further purification.LRMS (M+H⁺) m/z 272.1.

To a solution of 2 (6.9 g, 18 mmol) in DMF (30 mL) were added 3 (5.9 g,21.8 mmol) and N,N-diisopropylethylamine (9.5 mL, 54.3 mmol). Thereaction was monitored by LC/MS. After completion, 2 M methylamine inTHF (13.6 mL, 27 mmol), HOBt (4 g, 27 mmol), and HBTU (10 g, 27 mmol)were added to the reaction solution. The reaction was stirred for 4hours. The mixture was diluted with ethyl acetate (60 mL) and washedwith saturated NaHCO₃ (20 mL). The organic layer was separated, and theaqueous phase was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate, andconcentrated. The resulting crude product was purified via flash columnchromatography using a mixture of ethyl acetate and hexane as eluent togive 4 (cis isomer 808 mg, 1.68 mmol, trans isomer 300 mg, 0.63 mmol).LRMS (M+H⁺) m/z 481.1.

To a solution of 4 (290 mg, 0.6 mmol) in dichloromethane (20 mL) wasadded trifluoroacetic acid (5 mL). The resulting solution was stirred atroom temperature for 1 hour and then concentrated under reducedpressure. The residue was purified via flash column chromatography usinga mixture of 99% ethyl acetate and 1% acetic acid as eluent to give 5 asa white solid (140 mg, 55%). LRMS (M+H⁺) m/z 425.1.

To a solution of 5 (330 mg, 0.7 mmol) in DMSO (5 mL) were added ammoniumchloride (83 mg, 1.5 mmol), diisopropylethylamine (0.27 mL, 1.5 mmol),and HBTU (580 mg, 1.5 mmol). The resulting solution was stirred at roomtemperature for 15 hours. Additional ammonium chloride (37 mg, 0.7mmol), diisopropylethylamine (0.12 mL, 0.7 mmol), and HBTU (266 mg, 0.7mmol) were added. Stirring was continued for additional 5 hours, and themixture was diluted with ethyl acetate (50 mL) and washed with saturatedNaHCO₃ (20 mL). The organic layer was separated, and the aqueous phasewas extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, and concentrated toyield slightly yellow crude. The residue was purified by RP-HPLC using amixture of acetonitrile and H₂O to give 6 (128 mg, 30%). LRMS (M+H⁺) m/z424.1.

To a solution of 6 (94 mg, 0.2 mmol) in DMF (2 mL) was added cyanuricchloride (45 mg, 0.2 mmol) at 0° C., and the reaction micxture wasstirred under nitrogen. After 1 hour, the reaction solution wasconcentrated to give 7 (79 mg), which was used in the next step withoutfurther purification. LRMS (M+H⁺) m/z 406.1.

To a solution of 7 (17 mg, 0.04 mmol) in methanol (2 mL) was stirredunder a stream of HCl for 15 min. A stream of nitrogen was then bubbledthrough the reaction mixture. After 1 hour, the reaction solution wasconcentrated to give 8, which was used in the next step without furtherpurification. LRMS (M+H⁺) m/z 438.1.

To a solution of crude 8 (17 mg, ˜0.04 mmol) in acetic acid (2 mL) wasadded o-phenylenediamine(50 mg, 0.46 mmol), and the resulting solutionwas stirred at 80° C. for 1 h. The reaction mixture was concentrated andpurified via preparative thin layer chromatography using 5% methanol indichloromethane as eluent to give a white solid. The solid was purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 9 (9 mg,45%). LRMS (M+H⁺) m/z 497.1.

To a solution of 5 (50 mg, 0.12 mmol) in DMF (1 mL) were addedbenzylamine (16 mg, 0.14 mmol) and HATU (57 mg, 0.14 mmol). The reactionmixture was stirred at room temperature for 3 hours. The resultingsolution was filtered and the filtrate was purified by RP-HPLC using amixture of acetonitrile H₂O to give 6 (16 mg, 26%). LRMS (M+H⁺) m/z514.1.

To a solution of H-Phe(4-NHBoc)-OH (4.8 g, 17.1 mmol) in ethanol (60mL), methanol (20 mL), acetic acid (60 mL), and water (30 mL) was addedplatinum (IV) oxide (360 mg, 1.6 mmol). The reaction mixture was stirredunder a stream of H₂ (45 psi) for 20 hrs. The catalyst was removed byfiltration through a PTFE (0.45 μm) filter and the solvent evaporated togive 2 (5 g), which was used in the next step without furtherpurification. LRMS (M+H⁺) m/z 287.1.

To a solution of crude 2 (3.2 g, 11.2 mmol) in DMF (20 mL) were added 3(3.8 g, 10 mmol) and N,N-diisopropylethylamine (5.2 mL, 30 mmol). Thereaction was monitored by LC/MS. After completion, methylamine (2 M inTHF, 7.5 mL, 15 mmol), and HBTU (5.7 g, 15 mmol) were added to thereaction solution. The reaction was stirred overnight. The mixture wasdiluted with ethyl acetate (60 mL) and washed with saturated NaHCO₃ (20mL). The organic layer was separated, and the aqueous phase wasextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, and concentrated. Theresulting crude was purified via RP-HPLC using a mixture of acetonitrileand H₂O to give 4 (1.0 g, 18% from 1). LRMS (M+H⁺) m/z 496.1.

To a solution of 4 (1.0 g, 2.0 mmol) in dichloromethane (25 mL) wasadded trifluoroacetic acid (8 mL). The resulting solution was stirred atroom temperature for 4 hous and then concentrated under reducedpressure. The residue was purified via RP-HPLC using a mixture ofacetonitrile and H₂O to give 5 (820 mg, 79%). LRMS (M+H⁺) m/z 396.1.

To a solution of 5 (75 mg, 0.16 mmol) in THF (3 mL) were added4-fluorobenzoyl chloride (28 μL, 0.23 mmol) andN,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture wasstirred overnight. The resulting solution was concentrated and purifiedby RP-HPLC using a mixture of acetonitrile and H₂O to give 6 (65 mg,78%). LRMS (M+H⁺) m/z 518.1.

To a solution of 5 (75 mg, 0.16 mmol) in THF (3 mL) were added isobutylchloroformate (30 μL, 0.23 mmol) and N,N-diisopropylethylamine (100 μL,0.57 mmol). The reaction mixture was stirred overnight. The resultingsolution was concentrated and purified by RP-HPLC using a mixture ofacetonitrile and H₂O to give 7 (62 mg, 78%). LRMS (M+H⁺) m/z 496.1.

To a solution of 5 (75 mg, 0.16 mmol) in THF (3 mL) was added tert-butylisocyanate (26 μL, 0.23 mmol) and N,N-diisopropylethylamine (100 μL,0.57 mmol). The reaction mixture was stirred overnight. The resultingsolution was concentrated and purified by RP-HPLC using a mixture ofacetonitrile and H₂O to give 7 (55 mg, 69%). LRMS (M+H⁺) m/z 495.1.

Example 25

To a solution of Boc-L-serine-beta-lactone 28 (200 mg, 1.07 mmol) inacetonitrile (5 mL) was added 29 (154 mg, 1.07 mmol). The mixture wasstirred at 56° C. overnight and then concentrated under reduced pressureto give 30.

Crude 30 was redissolved in DMF (1 mL) and treated with methylamine (2 Min THF) (0.54 mL, 1.08 mmol) and HBTU (404 mg, 1.07 mmol). The mixturewas stirred for 1 hour, after which it was filtered, and the filtratepurified on reverse phase HPLC (C18) using a mixture of acetonitrile andH₂O to give 31 (50.0 g, 14%).

To a solution of 31 (50.0 g, 0.145 mmol) in dichloromethane (5 mL) wasadded TFA (5 mL) at room temperature. The reaction mixture was stirredfor 20 min. The solvents were evaporated under reduced pressure and theresidue re-suspended in DMF (100 mL) followed by the addition of 6 (66.3mg, 0.174 mmol) and diisopropylethylamine (51 uL, 0.290 mmol) at roomtemperature. The reaction mixture was stirred for 1 hour, thenconcentrated under reduced pressure, and the residue purified on a flashsilica gel soumn (hexane:EtOAc, 1:1) to give 32 (50.0 mg, 78.2%). LCMS(M+H⁺) m/z 441.1.

Example 26

To a solution of 40 (50.0 g, 0.0874 mmol) in water (1 mL) and methanol(1 mL) were added sodium EDTA (88.1 mg, 0.262 mmol) and Hg(OAc)₂ (83.7mg, 0.262 mmol). The reaction mixture was stirred at 100° C. for 1 h andthen concentrated under reduced pressure. The residue was purified on aflash silica gel column (DCM:MeOH, 10:1) to give 41 (29.6 mg, 71%). LCMS(M+H⁺) m/z 472.4.

Example 27

To a stirring solution of 51 (1.0 g, 8.76 mmol) in DMF (20 mL) wereadded 6 (3.34 g, 8.76 mmol) and diisopropylethylamine (2.30 mL, 13.1mmol) at room temperature. The reaction mixture was monitored by reversephase HPLC/MS. After completion, 2 M methylamine in THF (8.80 mL, 17.5mmol) and HBTU (4.97 g, 13.1 mmol) were added to the reaction solution.After stirring for 1 hour, the reaction mixture was concentrated andpurified on a flash silica gel column (hexane:EtOAc, 1:1) to give 53(1.0 g, 35.3%).

To a solution of 53 (1.0 g, 3.09 mmol) in ethanol (20 mL) were addedtriethylamine (0.517 mL, 3.71 mmol) and hydroxyamine hydrochloride (258mg, 3.71 mmol). After stirring at reflux for 24 hours, the solvents wereevaporated under reduced pressure. The residue was purified on reversephase HPLC (C18) using a mixture of acetonitrile and H₂O to give 54 (280mg, 25%).

To a stirred solution of 54 (280 mg, 0.785 mmol) in THF (50 mL) wereadded diisopropylethylamine (164 uL, 0.942 mmol) and benzoyl chloride(100 uL, 0.864 mmol) at room temperature. After stirring for 30 min, thereaction mixture was concentrated, the residue was dissolved in HOAc(100 mL), and the mixture was stirred at reflux for 5 hours. Thesolvents were removed under reduced pressure, and the residue waspurified on a flash silica gel column (hexane:EtOAc, 1:1) to give 56 (49mg, 14.1%). LCMS (M+H⁺) m/z 443.1.

Example 28

To a solution of 57 (3.0 g, 10.4 mmol) in DMF (50 mL) were added 58(1.69 g, 12.4 mmol) and HBTU (5.92 g, 15.6 mmol). The reaction mixturewas monitored by reverse phase HPLC/MS. After stirring 5 hours, thesolvents were evaporated under reduced pressure and the residue purifiedon a flash silica gel column (hexane:EtOAc, 1:1) to give 59 (3.50 g,82%).

To a solution of 59 (200 mg, 0.491 mmol) in toluene (5 mL) was addedLawesson's Reagent (109 mg, 0.270 mmol). After stirring at 100° C. for30 min, the solvents were evaporated under reduced pressure. The residuewas purified on a flash silica gel column (hexane:EtOAc, 1:1) to give 60(160 mg, 80%).

To a solution of 60 (150 mg, 0.431 mmol) in dichloromethane (5 mL) wasadded TFA (5 mL) at room temperature. The reaction mixture was stirredfor 2 hours. The solvents were evaporated under reduced pressure, andthe residue 61 (121 mg, 100%) was dried under vacuum overnight.

To a stirred solution of 61 (0.395 mmol) in DMF (5 mL) were added 6 (180mg, 0.473 mmol) and diisopropylethylamine (138 uL, 0.790 mmol) at roomtemperature. The reaction mixture was monitored by HPLC/MS. Aftercompletion, 2 M methylamine in THF (395 uL, 0.790 mmol) and HBTU (225mg, 0.593 mmol) were added to the reaction solution. The reactionmixture was stirred for 30 min, after which the mixture was filtered,and the filtrate purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 62 (70.0 mg, 38.6%). LCMS (M+H⁺) m/z 459.0.

Example 29

A solution of nitrile 1 (640 mg, 1.6 mmol) and MeOH (25 mL) at 0° C. wassaturated with HCl gas. The reaction vessel was allowed to warm to 23°C. After 2 h at 23° C. the reaction solution was concentrated in vacuoand the resulting residue 2 was used without further purification.

A solution of crude imidate 2 (50 mg, 0.12 mmol),2-amino-3-methyl-propanol (36 mg, 0.35 mmol), and THF (1 mL) was stirredat 80° C. for 30 min. The reaction mixture was then concentrated invacuo and the resulting residue was dissolved in EtOAc (10 mL) andwashed with 1 N NaOH (5 mL) and brine (5 mL). The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by flash column chromatography (silica gel, 100%EtOAc) to yield 25 mg (43%) of the oxazole 3. LRMS (M+H⁺) m/z 486.3.

Example 30

A solution of crude imidate 2 (50 mg, 0.12 mmol), phenylene diamine (36mg, 0.32 mmol), and acetic acid (1 mL) was stirred at 80° C. for 30 min.The reaction mixture was then concentrated in vacuo, and the resultingresidue was dissolved in EtOAc (10 mL) and washed with 1 N NaOH (5 mL)and brine (5 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:3 hexanes:EtOAc) to yield 20 mg(34%) of benzimidazole 3. LRMS (M+H⁺) m/z 491.2.

Example 31

A solution of bromide 4 (500 mg, 1.1 mmol), 4-methyl-1-pentyn-3-ol (0.15mL, 1.32 mmol), bis(triphenylphosphine)palladium(II) chloride (390 mg,0.55 mmol), copper iodide (52 mg, 0.28 mmol), triethylamine (5 mL), andDMF (10 mL) was stirred at 100° C. for 3 hours. The reaction mixture wasthen concentrated in vacuo and the resulting residue dissolved in EtOAc(50 mL) and washed with 0.1 N HCl (3×20 mL) and brine (20 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by flash column chromatography(silica gel, 1:1 hexanes:EtOAc) to yield 200 mg (42%) of acetylene 5.LRMS (M+H⁺) m/z 471.2.

A solution of alcohol 5 (50 mg, 0.12 mmol), Dess-Martin periodinane (90mg, 0.21 mmol), and CH₂Cl₂ (3 mL) was stirred at 23° C. for 2 hours. Thereaction mixture was diluted in EtOAc (20 mL), and washed with saturatedaqueous NaHCO₃ (10 mL) and brine (20 mL). The organic layer was dried(MgSO₄), filtered, and concentrated in vacuo. The resulting residue wasused directly.

A solution of crude ketone 6 (30 mg, 0.06 mmol), hydrazine (0.13 mL, 1.0M in THF), and DMF (1 mL) was stirred at 23° C. for 12 hours. Thereaction mixture was then diluted in EtOAc (10 mL), and washed with 0.1N HCl (5 mL) and brine (5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby reverse phase HPLC (C18, acetonitrile/water) to yield 5 mg (18%) ofpyrazine 7. LRMS (M+H⁺) m/z 483.2

Example 32

A solution of bromide 4 (500 mg, 1.1 mmol), bis(pinacolote)diboron (420mg, 1.65 mmol), potassium acetate (433 mg, 4.4 mmol),[1,1′-bis(diphenylphosphino) ferrocene]-dichloropalladium(II) (180 mg,0.22 mmol), and DMF (5 mL) was stirred at 80° C. for 3 min. Bromide 9(366 mg, 4.65 mmol) and Na₂CO₃ (4.4 mL, 2.0 M in H₂O) were then addedand the mixture stirred at 80° C. for 2 hours. The reaction mixture wasthen diluted in EtOAc (50 mL), the layers were separated, and theorganic layer was washed with 0.1 N HCl (10 mL) and brine (10 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by reverse phase HPLC (C18,acetonitrile/water) to yield 165 mg (28%) of thiazole 10. LRMS (M+H⁺)m/z 531.2.

A solution of ester 10 (165 mg, 0.31 mmol), potassium hydroxide (35 mg,0.62 mmol), H₂O (1 mL), MeOH (1 mL), and THF (2 mL) was stirred at 50°C. for 2 hours. The reaction mixture was then diluted with EtOAc (20mL), and washed with 1 N HCl (5 mL) and brine (10 mL). The organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo, and theresulting residue was used directly.

A solution of acid 11 (140 mg, 0.28 mmol), pentafluorophenoltrifluoroacetate 12 (96 μL, 0.56 mmol), triethylamine (77 μL, 0.56mmol), and DMF (4 mL) was stirred at 23° C. for 2 hours. The reactionmixture was then diluted with EtOAc (20 mL), and washed with 1 N HCl (5mL), saturated aqueous NaHCO₃ (5 mL) and brine (10 mL). The organiclayer was dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography (silicagel, 1:1 hexanes:EtOAc) to yield 80 mg of ester 13.

A solution of ester 13 (20 mg, 0.03 mmol), isopropyl amine (5 μL, 0.06mmol), and THF (1 mL) was stirred at 23° C. for 12 hours. The reactionmixture was then diluted with EtOAc (20 mL), and washed with 1 N HCl (5mL), saturated aqueous NaHCO₃ (5 mL) and brine (10 mL). The organiclayer was dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography (silicagel, 1:3 hexanes:EtOAc) to yield 9 mg (55%) of the amide 14. LRMS (M+H⁺)m/z 543.2.

Example 33

A solution of imidate 2 (1.6 g, 4.0 mmol) and 2.0 M NH₃ in MeOH (10 mL)was stirred at 23° C. for 12 hr. The reaction mixture was thenconcentrated in vacuo and the resulting residue was purified by flashcolumn chromatography (silica gel, 1:10 CH₂Cl₂:MeOH) to yield 1.3 g(78%) of amidine 17. LRMS (M+H⁺) m/z 417.2

A solution of amidine 17 (50 mg, 0.12 mmol), methyl isobutyrylacetate(17 μL, 0.12 mmol), and NaOMe (0.5 M in MeOH, 0.72 mL) was stirred at120° C. for 1 hr. The reaction mixture was then concentrated in vacuoand the resulting residue purified by reverse phase HPLC (C18,acetonitrile/water) to yield 10 mg (16%) of pyrimidine 18. LRMS (M+H⁺)m/z 511.2.

A solution of bromide 4 (1.0 g, 2.20 mol),dichlorobis(triphenylphosphine)palladium(II) (154 mg, 0.220 mol),tributyl( 1-ethoxyvinyl)tin (1.49 ml, 4.41 mmol), and toluene (15 mL)under N₂ was stirred at 100° C. for 6 hours. Upon completion, asmonitored by LCMS, the reaction mixture was cooled, filtered throughCelite, and concentrated in vacuo. The resulting residue was purified byflash column chromatography (silica gel, 2:1:0.1 EtOAc: hexanes:triethylamine) to give 540 mg (55%) of styrene 19. LRMS (M+H⁺) m/z445.2.

A solution of compound 19 (540 mg, 1.21.mmol), THF:H₂O (3:1, 12 mL), andN-bromo-succinimide (216 mg, 1.21 mmol) was stirred at 23° C. for 15min. The reaction mixture was then concentrated in vacuo and the cruderesidue diluted with EtOAc (30 mL), washed with brine (10 mL), andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:1 EtOAc:hexanes) to give 210 mg(35%) of bromoketone 20. LRMS (M+H⁺) m/z 495.1.

A solution of bromoketone 20 (210 mg, 0.42 mmol), K₂CO₃ (174 mg 1.26mmol), tert-butylcarbamidine hydrochloride (115 mg, 0.84 mmol), and DMF(4 mL) was stirred at 23° C. under N₂ for 18 hours. The reaction mixturewas concentrated under high vacuum (0.1 mm Hg), and the resultingresidue was purified by column chromatography (silica gel, 4:1EtOAc:hexanes) to give 50 mg (24%) of imidazole 21. LRMS (M+H⁺) m/z497.2.

A solution of bromoketone 20 (25 mg, 0.05 mmol), K₂CO₃ (14 mg 0.1 mmol),acetamide (6 mg, 0.1 mmol), and DMF (1 mL) was stirred at 100° C. for 4hours. The reaction mixture was diluted with EtOAc (15 mL), washed withbrine (3×10 mL), and concentrated in vacuo. The resulting residue waspurified by column chromatography (silica gel, 2:1 EtOAc:hexanes) togive 5 mg (22%) of oxazole 22. LRMS (M+H⁺) m/z 446.2.

A solution of bromoketone 20 (25 mg, 0.05 mmol), K₂CO₃ (14 mg 0.1 mmol),cyanothioacetamide (10 mg, 0.1 mmol), and DMF (1 mL) was stirred at 100°C. for 4 hours. The reaction mixture was diluted with EtOAc (15 mL),washed with brine (3×10 mL), and concentrated in vacuo. The resultingresidue was purified by reverse phase HPLC (C18, acetonitrile/water) togive 5 mg (20%) of thiazole 23. LRMS (M+H⁺) m/z 497.2.

A solution of bromoketone 20 (30 mg, 0.06 mmol), K₂CO₃ (25 mg 0.18mmol), phenylthiourea (18 mg, 0.12 mmol), and DMF (1 mL) was stirred at100° C. for 4 hours. The reaction mixture was diluted with EtOAc (15mL), washed with brine (3×10 mL), and concentrated in vacuo. Theresulting residue was purified by reverse phase HPLC (C18,acetonitrile/water) to give 10 mg (30%) of aminothiazole 24. LRMS (M+H⁺)m/z 549.2.

A solution of aniline 25 (100 mg, 0.25 mmol), concentrated HCl (1 mL),and AcOH (1 mL) was cooled to −5° C. NaNO₂ (20 mg, 0.29 mmol) was thenadded slowly to the solution over 1 min. The reaction solution wasstirred at −5° C. for 45 min to provide a solution of the diazoniumsalt.

In another reaction vessel, SO₂ was bubbled through a solution of AcOH(1 mL) and copper(I)chloride (6 mg, 0.06 mmol) until a blue-green colorpersisted. The diazonium solution was then added slowly over 1 min tothe SO₂/CuCl solution. The internal temperature of the stirred reactionsolution was maintained below 30° C. The resulting reaction mixture wasthen poured into cold H₂O (10 mL), extracted with diethyl ether (3×10mL), and the organic layer was dried (MgSO₄), filtered, and concentratedin vacuo. The crude sulfonyl chloride 26 was used without furtherpurification.

A solution of sulfonyl chloride 26 (74 mg, 0.16 mmol), diisopropylethylamine (81 mL, 0.16 mmol), benzylamine (17 mL, 0.16 mmol) and THF (1mL) was stirred at 23° C. for 18 hours. The reaction mixture was dilutedwith EtOAc (15 mL), washed with brine (3×10 mL), and concentrated invacuo. The resulting residue was purified by column chromatography(silica gel, 1:1 EtOAc:hexanes) to give 25 mg (29%) of sulfonamide 27.LRMS (M+H⁺) m/z 544.2

A solution of amino acid 64 (2.20 g, 8.27 mmol), pentafluorophenyl ester28 (3.0 g, 7.88 mmol), diisopropylethylamine (5.5 mL, 31.5 mmol), andDMF (30 mL) was stirred at 23° C. After 18 hours, H₂NMe (2.0 M in THF,3.94 mL),O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU, 6.0 g, 15.76 mmol) was added. After 4 hours, the reactionsolution was dissolved in EtOAc (200 mL), washed with brine (3×200 mL),and concentrated in vacuo. The resulting residue was purified by columnchromatography (silica gel, 2:1 EtOAc:hexanes) to give 3.5 g (93%) ofamide 30. LRMS (M+H⁺) m/z 475.2.

A solution of ester 66 (3.5 g, 7.36 mmol), TFA:H₂O (97.5:2.5, 10 mL),and CH₂Cl₂ (10 mL) was stirred at 23° C. for 3 hrs. The reactionsolution was concentrated in vacuo, and the resulting residue was placedunder high vacuum for 2 hours.

A solution of crude acid 67 (4.7 g, 11.2 mmol), pentafluorophenoltrifluoroacetate 12 (3.86 mL, 22.4 mmol), triethylamine (4.7 mL, 33.6mmol), and DMF (25 mL) was stirred at 23° C. for 18 hours. The reactionmixture was then diluted with EtOAc (200 mL), and washed with 1 N HCl(50 mL), saturated aqueous NaHCO₃ (50 mL) and brine, (100 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by flash column chromatography(silica gel, 2:1 hexanes:EtOAc) to yield 1.1 g (17%) of ester 68.

A solution of ester 68 (20 mg, 0.03 mmol), benzylamine (6 μL, 0.05mmol), and THF (0.5 mL) was stirred at 23° C. for 18 hours. The reactionmixture was then diluted with EtOAc (10 mL), and washed with 1 N HCl (5mL), saturated aqueous NaHCO₃ (5 mL) and brine (5 mL). The organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by reverse phase HPLC (C18, acetonitrile/water) toyield 13 mg (85%) of amide 14. LRMS (M+H⁺) m/z 508.2.

A solution of ester 66 (50 mg, 0.1 mmol), LiAlH₄ (1.0 M in THF, 0.21mL), and THF (1 mL) was stirred at 23° C. for 2 hours. The reactionmixture was quenched with MeOH (1 mL), then diluted with EtOAc (10 mL),washed with 1 N HCl (5 mL), and brine (5 mL). The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by reverse phase HPLC (C18, acetonitrile/water) toyield 2 mg (5%) of alcohol 70. LRMS (M+H+) m/z 405.2.

A solution of nitrile 71 (108 mg, 0.27 mmol), LiAlH₄ (1.0 M in THF, 0.1mL), and THF (2 mL) was stirred at 23° C. for 2 hours. The reactionmixture was quenched with MeOH (1 mL), then diluted with EtOAc (10 mL),washed with 1 N HCl (5 mL), and brine (5 mL). The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by reverse phase HPLC (C18, acetonitrile/water) toyield 30 mg (28%) of amine 72. LRMS (M+H⁺) m/z 404.2.

A solution of amine 72 (10 mg, 0.02 mmol), benzoyl chloride (3.2 μL,0.03 mmol), triethylamine (50 μL, 0.36 mmol), and CH₂Cl₂ (0.5 mL) wasstirred at 23° C. for 2 hours. The reaction mixture was then dilutedwith EtOAc (15 mL), and washed with 1 N HCl (2 mL), saturated aqueousNaHCO₃ (2 mL) and brine (5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography (silica gel, 2:1 hexanes:EtOAc) to yield5 mg (49%) of amide 73. LRMS (M+H⁺) m/z 508.2.

A solution of nitrile 71 (300 mg, 0.75 mmol), hydroxylaminehydrochloride (156 mg, 2.25 mmol), K₂CO₃ (726 mg, 5.25 mmol), and EtOH(10 mL) was stirred at 80° C. for 18 hours. The reaction mixture wasconcentrated in vacuo and the resulting residue diluted with EtOAc (15mL) and washed with brine (5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography (silica gel, 1:20 MeOH:EtOAc) to yield 80mg (250/o) of hydroxyamidine 74. LRMS (M+H⁺) m/z 433.2.

A solution of hydroxyamidine 74 (20 mg, 0.05 mmol), carbonyldiimidazole(CDI, 15 mg, 0.09 mmol), triethylamine (13 μL, 0.09 mmol), and DMF (1mL) was stirred at 100° C. for 2 hours. The resulting residue wasdiluted with EtOAc (15 mL) and washed with brine (3×5 mL). The organiclayer was dried (MgSO₄), filtered, and concentrated in-vacuo. Theresulting residue was purified by flash column chromatography (silicagel, 1:20 MeOH:EtOAc) to yield 10 mg (44%) of oxadiazolone 75. LRMS(M+H⁺) m/z 459.2.

A solution of amidoxime 74 (20 mg, 0.05 mmol), triethylamine (13 μL,0.09 mmol), acetic anhydride (0.5 mL), and DMF (0.5 mL) was stirred at100° C. for 2 hours. The resulting residue was diluted with EtOAc (15mL) and washed with brine (3×5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography (silica gel, 1:20 MeOH:EtOAc) to yield 13mg (57%) of oxadiazole 75. LRMS (M+H⁺) m/z 457.2.

Example 44

To a solution of 63 (100 mg, 0.367 mmol) in dichloromethane (10 mL) wereadded benzoyl chloride 64 (93.8 uL, 0.808 mmol) anddiisopropylethylamine (192 uL, 1.10 mmol). After stirring for 10 min, 2M methylamine in THF (550 uL, 1.10 mmol) was added to the reactionsolution. The reaction mixture was stirred for 30 min and concentrated.The residue was purified on a flash silica gel column (hexane:EtOAc,1:1) to give 66 (100 mg, 70%).

To a solution of 66 (100 mg, 0.257 mmol) in dichloromethane (5 mL) wasadded TFA (5 mL) at room temperature. The reaction mixture was stirredfor 100 min. The solvents were evaporated under reduced pressure, andthe residue dried under high vacuum overnight.

The residue was dissolved in DMF (2 mL) and then stirred with 6 (117 mg,0.308 mmol) and diisopropylethylamine (90.0 uL, 0.515 mmol) at roomtemperature. The reaction mixture was monitored by reverse phaseHPLC/MS. The reaction mixture was stirred for 30 min, after which it wasfiltered, and the filtrate purified by reverse phase HPLC (C18) using amixture of acetonitrile and H₂O to give 67 (100 mg, 52.9%). LCMS (M+H⁺)m/z 486.2.

Example 45

To a solution of 68 (500 mg, 1.23 mmol) in dichloromethane (10 mL) wasadded TFA (10 mL) at room temperature. The reaction mixture was stirredfor 10 min, and then the solvents were evaporated under reducedpressure. The resulting residue (˜1.23 mmol) was resuspended in DMF (50mL) to which was added 6 (562 mg, 1.48 mmol) and diisopropylethylamine(429 uL, 2.46 mmol) at room temperature. The reaction mixture wasmonitored by reverse phase HPLC/MS. After starting material was nolonger observed, 2 M methylamine in THF (1.23 mL, 2.46 mmol) and HBTU(702 mg, 1.85 mmol) were added to the solution. After stirring for 30min, the solvents were evaporated under reduced pressure and the residuepurified on a flash silica gel column (hexane:EtOAc, 1:1) to give 69(450 g, 71%). LCMS (M+H⁺) m/z 516.2.

69 (400 mg, 0.775 mmol) was dissolved in HBr/HOAc solution (10 mL).After stirring for 10 min, the solvents were removed. The residue wasdissolved in sodium bicarbonate solution (50 mL), and extracted withdichloromethane (50 mL) three times. The combined dichloromethane layerswere dried over sodium sulfate and filtered, and the filtrateconcentrated under reduced pressure to give 70 (285 mg, 96%).

To a solution of 70 (82.5 g, 0.216 mmol) in DMF (2 mL) were added benzylbromide (30.8 uL, 0.259 mmol) and diisopropylethylamine (75.3 uL, 0.432mmol). The reaction mixture was monitored by reverse phase HPLC/MS.After stirring for 2 hours, the mixture was filtered and the filtratepurified by reverse phase HPLC (C18) using a mixture of acetonitrile andH₂O to give 71 (183 mg, 90%). LCMS (M+H⁺) m/z 472.1.

To a solution of 71 (128 mg, 0.271 mmol) in water (1 mL) and methanol (1mL) were added sodium EDTA (273 mg, 0.814 mmol), HOAc (20 uL) andHg(OAc)₂ (259 mg, 0.814 mmol). The reaction mixture was stirred at 100°C. for 8 h, after which the solvents were evaporated under reducedpressure. The residue was re-dissolved in DMF (2 mL) and filtered, andthe filtrate was purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 72 (37.6 mg, 28.5%). LCMS (M+H⁺) m/z 486.1.

Example 46

To a solution of 42 (1.0 g, 3.24 mmol) in methanol/water (2/1, 20 mL)was added sodium bicarbonate (327 mg, 3.24 mmol). While stirring over anice-bath, bromine (200 uL, 3.89 mmol) was added dropwise into thereaction mixture. The reaction mixture was monitored by reverse phaseHPLC/MS. After starting material was no longer observed, the solventswere evaporated under reduced pressure. The residue was dissolved inwater (100 mL), and extracted with dichloromethane (50 mL) three times.The combined dichloromethane layers were dried over sodium sulfate, themixture was filtered, and the filtrate was concentrated to give 43.

To a solution of crude 43 (3.24 mmol) in methanol (50 mL) were addeddiisopropylethylamine (1.14 mL, 6.48 mmol) and benzyl thioamide 44 (445mg, 3.24 mmol). After stirring at reflux for 24 hours, the solvents wereevaporated under reduced pressure. The residue was purified by reversedphase HPLC (C18) using a mixture of acetonitrile and H₂O to give 45 (200mg, 18%).

To a solution of 45 (150 mg, 0.431 mmol) in dichloromethane (5 mL) wasadded TFA (5 mL) at room temperature. The reaction mixture was stirredfor 10 min. The solvents were then evaporated under reduced pressure,and the residue was dried under high vacuum overnight to give 46 (107mg, 100%).

To a stirred solution of 46 (0.431 mmol) in DMF (20 mL) were added 6(197 mg, 0.517 mmol) and diisopropylethylamine (150 uL, 0.862 mmol) atroom temperature. The reaction mixture was monitored by reverse phaseHPLC/MS. After starting material was no longer observed, 2 M methylaminein THF (0.431 mL, 0.862 mmol) and HBTU (245 mg, 0.647 mmol) were addedto the solution. The reaction mixture was stirred for 30 min, afterwhich the mixture was filtered, and the filtrate purified by reversedphase HPLC (C18) using a mixture of acetonitrile and H₂O to give 47(80.0 mg, 40.5% ). LCMS (M+H⁺) m/z 458.1.

The same procedures applied to 47 were used for making 50 (58.3 mg).LCMS (M+H⁺) m/z 441.4.

Example 47

To a stirred solution of Boc-p-biphenylalanine 9 (3.0 g, 8.79 mmol) inTHF (200 mL) over an ice bath was added LAH (1.0 M in THF, 17.6 mL, 17.6mmol). After stirring for 2 hours, the reaction was quenched with MeOH(10 mL) followed by NaOH solution (17.6 mL, 35.1 mmol). The mixture wasfiltered through Celite® and the filtrate concentrated under reducedpressure. The residue was dissolved in water (200 mL) and extracted withDCM (200 mL) three times. The combined dichloromethane layers were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to give 10(2.85 g, 98%).

To a stirred solution of 10 (2.85 g, 8.70 mmol) in THF (250 mL) wereadded 11 (1.54 g, 10.4 mmol) and triphenylphosphine (2.51 g, 9.57 mmol).DEAD (1.49 mL, 9.57 mmol) was then added dropwise and the reactionstirred for 30 min. The mixture was concentrated in vacuo, and theresidue was purified on a flash silica gel column (hexane:EtOAc, 6:1) toobtain the product 12 (2.0 g, 50%).

To a solution of 12 (2.0 g, 4.38 mmol) in dichloromethane (50 mL) wasadded TFA (50 mL) at room temperature. The reaction mixture was stirredfor 20 min and then concentrated in vacuo to give 13 (1.56 g 100%).

To a solution of 13 in DMF (100 mL) were added 6 (2.0 g, 5.26 mmol) anddiisopropylethylamine (1.53 mL, 8.76 mmol) at room temperature. Thereaction mixture was stirred overnight. The solvents were evaporatedunder reduced pressure and the residue purified over silica gel(hexane:EtOAc=2:1) to give 14 (1.5 g, 61.9%). LRMS (M+H⁺) m/z 553.1.

To a solution of 14 (1.5 g, 2.71 mmol) in methanol (20 mL) was addedhydrazine hydrate (0.845 mL, 27.1 mmol). The reaction mixture wasstirred at 50° C. for 5 h, and then cooled to room temperature. Thesolid was filtered off, and the filtrate was concentrated under reducedpressure to give 15 (1.0 g, 87.2%). LCMS (M+H⁺) m/z 423.1.

Example 48

To a solution of 15 (20.0 mg, 0.0473 mmol) in dichloromethane (10 mL)were added diisopropylethylamine (24.7 uL, 0.142 mmol) and acetylchloride (5.0 uL, 0.0709 mmol). The reaction mixture was stirred for 10min, then concentrated under reduced pressure and purified by reversephase HPLC (C18) using a mixture of acetonitrile and H₂O to give 16 (8.0mg, 36.4%). LCMS (M+H⁺) m/z 465.2.

To a solution of 15 (60.0 mg, 0.142 mmol) in dichloromethane (2 mL) wereadded diisopropylethylamine (49.5 uL, 0.282 mmol), 17 (32.2 mg, 0.170mmol) and HBTU (80.8 mg, 0.213 mmol). The reaction mixture was stirredfor 10 min and then concentrated under reduced pressure. The resultingresidue was dissolved in dichloromethane (1 mL) and TFA (1 mL) andstirred for 10 min, then concentrated under reduced pressure and theproduct purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 19 (25.0 mg, 35.6%). LCMS (M+H⁺) m/z 494.2.

To a solution of 15 (35.0 mg, 0.0828 mmol) in dichloromethane (2 mL)were added diisopropylethylamine (28.8 uL, 0.166 mmol) andmethanosulfonyl chloride (9.64 uL, 0.124 mmol). The reaction mixture wasstirred for 10 min, then concentrated under reduced pressure and productpurified on reverse phase HPLC (C18) using a mixture of acetonitrile andH₂O to give 20 (25.0 mg, 60.3%). LCMS (M+H⁺) m/z 501.2.

To a solution of 15 (60.0 mg, 0.142 mmol) in dichloromethane (2 mL) wereadded diisopropylethylamine (49.5 uL, 0.282 mmol) andtrimethylsiliylisocyanide (19.6 mg, 0.170 mmol). The reaction mixturewas stirred for 10 min, then concentrated under reduced pressure and theproduct purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 21 (20.6 mg, 31.1%). LCMS (M+H⁺) m/z 466.1.

To a solution of 15 (60.0 mg, 0.142 mmol) in dichloromethane (2 mL) wereadded diisopropylethylamine (49.5 uL, 0.282 mmol) and methylchloroformate (13.1 uL, 0.170 mmol). The reaction mixture was stirredfor 10 min, then concentrated under reduced pressure and the residuepurified by reverse phase HPLC (C18) using a mixture of acetonitrile andH₂O to give 22 (19.9 mg, 29.1%). LCMS (M+H⁺) m/z 481.1.

Example 49

A solution of 4-bromobenzaldehyde (14.8 g, 80 mmol) and ammonium acetate(14.0 g, 180 mmol) in nitroethane (50.0 g) was heated to reflux for 8hours. It was then cooled to room temperature and partitioned betweendichloromethane (150 mL) and water (30 mL). The phases were separatedafter which the organic layer was dried over sodium sulfate andconcentrated in vacuo. The residue was passed down a plug silica gelcolumn (ethyl acetate/hexane as eluent) followed by recrystallizationfrom methanol to yield intermediate 2 (9.8 g, 51%), which was determinedto be pure enough for use in subsequent transformations (LC/MS (LRMS(M+H⁺) m/z: 240.97).

To a 0° C. solution of sodium borohydride (4.6 g, 124 mmol) intetrahydrofuran (100 mL) was added borane-tetrahydrofuran complex (150mL, 150 mmol, 1.0 M). The resulting solution was then stirred at roomtemperature for an additional 15 minutes. Intermediate 2 (6.5 g, 27mmol) in tetrahydrofuran (30 mL) was added dropwise, and the resultingsolution was refluxed for 4 hours. It was cooled to room temperature andthe reaction quenched with water and extracted with dichloromethane(3×80 mL). The combined organic layers were dried over sodium sulfateand concentrated in vacuo, and the residue was purified by flashchromatography (silica gel, hexane/ethyl acetate) to provideintermediate 3 (5.2 g, 90%), which was characterized by LC/MS (LRMS(M+H⁺) m/z: 213.02).

A 0° C. solution of amine 3 (4.0 g, 16 mmol) in ethyl acetate (30 mL)was saturated with hydrochloric acid (gas). The resulting salt wascollected by filtration and dried in vacuo.

L-N-Acetylleucine sodium salt (8.0 mmol) (prepared by addition of 1 Nsodium hydroxide solution to a suspension of L-N-acetylleucine (1.39 g,8.0 mmol) in 5 mL of water until pH=7) was added slowly to a stirredsolution of the aforementioned 3 hydrochloride salt in water (10 mL).Crystals formed overnight and were removed by filtration, washed with asmall amount of cold water, and recrystallized from absolute methanol.The crystalline 4a salt was collected and dried in vacuo.

The mother liquors, which were rich in (S)-3, were combined, madestrongly alkaline with 5 N sodium hydroxide solution, and washed threetimes with diethyl ether. The combined organic layers were washed withwater and dried over sodium sulfate. After removal of sodium sulfate,hydrochloric acid was passed through the solution until theprecipitation of hydrochloride salt was complete. The same procedure asabove was applied with D-N-acetylleucine salt. The crystalline 4b saltwas collected and dried in vacuo.

The diastereomeric salt of each enantiomer was partitioned between 20 mLof water, made strongly alkaline with 5 N sodium hydroxide solutions,and extracted with diethyl ether. The combined organic layers werewashed with water and dried over sodium sulfate. The solvents wereremoved, and both products were determined to be pure enough for use insubsequent transformations (4a: 1.3 g, 32%; 4b: 0.9 g, 22%) (¹H-NMR andLC/MS (LRMS (M+H⁺) m/z: 213.02)). Capillary electrophoresisindicated >98% ee.

To a room temperature solution of amine 4a (111 mg, 0.52 mmol) indimethylformamide (5 mL) was added diisopropylethylamine (99 μL, 0.57mmol). The resulting solution was stirred for 5 minutes and intermediate5 (217 mg, 0.57 mmol) was added. The reaction mixture was stirred underan atmosphere of nitrogen for 30 minutes and the solvents were removedin vacuo. The residue was partitioned between ethyl acetate (20 mL) andaqueous citric acid solution (20 mL, 10%). The layers were separated,and the organic phase was washed with aqueous citric acid solution (20mL, 10%) and aqueous potassium hydroxide solution (2×20 mL, 0.1 M). Itwas then dried over sodium sulfate and concentration in vacuo to yield 6(212 mg, 100%), which was determined to be pure enough for use insubsequent transformations (LRMS (M+H⁺) m/z: 410.1).

To a room temperature solution of bromide 6 (212 mg, 0.53 mmol) indioxane (10 mL) were addedtrans-dichlorobis(triphenylphosphine)palladium(II) (37 mg, 10 mol %) and1-ethoxyvinyltri-n-butyltin (481 mg, 1.33 mmol), successively. Theresulting solution was heated to 100° C. for 4 hours. It was cooled toroom temperature and the solvents were removed in vacuo. The residue wasthen purified by flash chromatography (silica gel, ethyl acetate plus 5%triethylamine) to provide intermediate 7 (250 mg) which was unstable anddetermined to be pure enough for use in subsequent transformations LC/MS(LRMS (M+H⁺) m/z: 402.8).

Intermediate 7 in tetrahydrofuran (10 mL) and water (3 mL) was stirredwith N-bromosuccinimide (190 mg, 1.1 mmol) at 50° C. for 2 hours. Thesolvents were removed in vacuo, and the resulting residue waspartitioned between water (10 mL) and extracted with ethyl acetate (3×50mL). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was then purified by flashchromatography (silica gel, hexane/ethyl acetate) to provideintermediate 8 (55 mg, 23%), which was characterized by LC/MS (LRMS(M+H⁺) m/z: 452.1).

To a room temperature solution of intermediate 9 (55 mg, 0.12 mmol) indimethylformamide (3 mL) was added potassium carbonate (34 mg, 0.24mmol) and tert-butylcarbamidine (31 mg, 0.30 mmol). The reaction mixturewas stirred under an atmosphere of nitrogen at 50° C. for 1.5 hours. Itwas cooled to room temperature and the solvents were removed in vacuo.The residue was partitioned between ethyl acetate (15 mL) and water (15mL). The layers were separated and the aqueous phase was extracted withethyl acetate (2×20 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was then purifiedby flash chromatography (silica gel, hexane/ethyl acetate) to provide 9(35 mg, 67%), which was characterized by ¹H NMR and LC/MS (LRMS (M+H⁺)m/z: 452.1).

Example 50

To a room temperature solution of acid 1 (2.98 g, 9.2 mmol) in methanol(15 mL) was added dropwise a solution of TMS diazomethane in hexanes(9.2 mL, 18.4 mmol, 2.0 M). The resulting yellow solution was stirred atambient temperature for 30 minutes, and the solvents were removed invacuo. The residual viscous oil 2 (3.10 g, 9.2 mmol) was dried anddetermined to be pure enough for use in subsequent transformations.LC/MS (M+H⁺) m/z: 339.10.

A mixture of intermediate 2 (3.10 g, 9.2 mmol) and palladium on carbon(310 mg) in methanol (30 mL) was stirred under hydrogen at roomtemperature for 2 hours. It was then filtered through Celite® andconcentrated to provide aniline 3 (2.47 g, 8.0 mmol) as a viscous oil,which was dried and determined to be pure enough for use in subsequenttransformations. LC/MS (M+H⁺) m/z: 309.20.

To a room temperature solution of aniline 3 (2.47 g, 8.0 mmol) indichloromethane (20 mL) was added trifluoroacetic acid (20 mL). Theresulting solution was stirred for 45 minutes, and the solvents wereremoved in vacuo. The residue was partitioned between dichloromethane(75 mL) and saturated aqueous sodium bicarbonate solution (25 mL), andthe layers were separated. The aqueous phase was saturated with sodiumchloride and extracted with dichloromethane (3×75 mL) andtetrahydrofuran (2×50 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo to provide 4 (1.30 g, 6.3 mmol)as a viscous oil, which was characterized by LC/MS (LRMS (MH) m/z:209.30).

A solution of amine 4 (1.30 g, 6.25 mmol) in dimethylformamide (20 mL)was stirred with diisopropylethylamine (3.27 mL, 18.80 mmol) at roomtemperature for 5 minutes, followed by the addition of intermediate 5(2.38 g, 6.25 mmol). The reaction mixture was stirred for an additional30 minutes, and the solvents were removed in vacuo. The residue waspartitioned between ethyl acetate (50 mL) and water (50 mL). The layerswere separated, and the aqueous phase was extracted with ethyl acetate(3×50 mL). The combined organic layers were dried over sodium sulfateand concentrated in vacuo. The residue was purified by flashchromatography (silica gel, hexane/ethyl acetate) to provide 6 (1.47 g,58%) as a foamy white solid, which was characterized by LC/MS (LRMS(M+H⁺) m/z: 405.15).

To a room temperature solution of aniline 6 (131 mg, 0.32 mmol) intetrahydrofuran (5 mL) were added diisopropylethylamine (85 μL, 0.48mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol), anddi-tert-butyldicarbonate (85 mg, 0.39 mmol). The resulting solution wasstirred overnight and then diluted with ethyl acetate (20 mL), washedwith aqueous hydrochloric acid solution (2×15 mL, 0.1 M) and dried oversodium sulfate. Removal of solvents yielded carbamate 7 (139 mg, 88%) asa glassy solid, which was determined to be pure enough for use insubsequent transformations. LC/MS (LRMS (M+H⁺) m/z: 505.10).

To a room temperature solution of carbamate 7 (139 mg, 0.28 mmol) inmethanol (2 mL) and tetrahydrofuran (2 mL) was added sodium borohydride(261 mg, 6.9 mmol). The resulting mixture was stirred for 2 hours, afterwhich the solvents were removed in vacuo. The residue was partitionedbetween ethyl acetate (15 mL) and water (15 mL), the layers wereseparated, and the aqueous phase was extracted with ethyl acetate (3×15mL). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by reverse-phase HPLCusing a mobile phase gradient consisting of acetonitrile and water. Thepure product 8 (47 mg, 36%) was isolated and characterized by ¹H-NMR andLC/MS (LRMS (M+H⁺) m/z: 477.20).

To a 0° C. solution of triphosgene (37 mg, 0.13 mmol) in tetrahydrofuran(15 mL) was added dropwise a solution of 6 (145 mg, 0.36 mmol) anddiisopropylethylamine (130 μL, 0.75 mmol) in tetrahydrofuran (5 mL). Theresulting mixture was kept under an atmosphere of nitrogen at the sametemperature for 30 minutes and quenched with methyl-tert-butylamine (215μL, 1.80 mmol). The reaction mixture was stirred for an additional 30minutes followed by removal of the solvents in vacuo. The residue waspartitioned between ethyl acetate (15 mL) and aqueous hydrochloric acidsolution (15 mL, 0.1 M), the layers were separated, and the aqueousphase was extracted with ethyl acetate (2×15 mL). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo to yieldurea 9 (152 mg, 0.29 mmol) as a glassy solid, which was determined to bepure enough for use in subsequent transformations. LC/MS (LRMS (M+H⁺)m/z: 518.2).

To a room temperature solution of urea 9 (150 mg, 0.29 mmol) in methanol(2 mL) and tetrahydrofuran (2 mL) was added sodium borohydride (260 mg,6.90 mmol). The resulting mixture was stirred under an atmosphere ofnitrogen at room temperature for 2 hours. The solvents were removed andthe residue was partitioned between ethyl acetate (15 mL) and water (15mL). The layers were separated and the aqueous phase was extracted withethyl acetate (3×15 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified byreverse-phase HPLC using a mobile phase gradient consisting ofacetonitrile and water. The pure product 10 (4 mg, 28%) was isolated andcharacterized by ¹H-NMR and LC/MS (LRMS (M+H⁺) m/z: 490.1).

Example 51

To a solution of carboxylic acid 1 (10.0 g, 28 mmol) in anhydrousdiethyl ether (200 mL) at 0° C. was added dropwise a solution of lithiumaluminum hydride in tetrahydrofuran (40 mL, 40 mmol, 1 M). The resultingsolution was then stirred for an additional 2 hours at the sametemperature. It was carefully quenched with water (2.5 mL), aqueoussodium hydroxide (2.5 mL, 1 M) and water (3.0 mL). The solution was thendried over sodium sulfate, and removal of the solvents yieldedintermediate 2 (9.2 g, 96%), which was determined to be pure enough foruse in subsequent transformations. Characterization was carried out with¹H-NMR and LC/MS (LRMS (M+H⁺) m/z: 344.08).

To a room temperature solution of intermediate 2 in anhydrous dioxane(200 mL) were added triethylamine (6 mL, 40 mmol) andtert-butyldimethylsilyltrifluoro methanesulfonate (8.6 g, 32 mmol). Theresulting solution was then stirred overnight and quenched withsaturated aqueous sodium bicarbonate solution. It was extracted withdichloromethane (3×100 mL), and the combined organic layers were driedover sodium sulfate and concentrate in vacuo. The residue was purifiedby flash chromatography (silica gel, hexane/ethyl acetate) to provideintermediate 3 (9.2 g, 72% overall), which was characterized by LC/MS(LRMS (M+H⁺) m/z: 458.16).

To a room temperature solution of bromide 3 (6.0 g, 13 mmol) in dioxane(100 mL) were added trans-dichlorobis(triphenylphosphine)palladium(II)(500 mg) and 1-ethoxyvinyltri-n-butyltin (12.3 g, 34 mmol),successively. The resulting solution was heated to 100° C. for 4 hours.Removal of the solvents in vacuo was followed by purification by flashchromatography (silica gel, hexane/ethyl acetate plus 5% triethylamine)to provide intermediate 4 (5.4 g) which was characterized by LC/MS (LRMS(M+H⁺) m/z: 450.30). The product was found to be unstable and usedimmediately in subsequent transformations.

Intermediate 4 in methanol (100 mL) and water (50 mL) was stirred withN-bromosuccinimide (5.9 g, 33 mmol) at 50° C. for 4 hours. The solventswere removed in vacuo, and the resulting residue extracted with ethylacetate (3×50 mL). The combined organic layers were dried over sodiumsulfate and concentrate in vacuo. The residue was then purified by flashchromatography (silica gel, hexane/ethyl acetate) to provideintermediate 5 (4.5 g, 69% overall), which was characterized by LC/MS(LRMS (M+H⁺) m/z: 500.54).

Under a nitrogen atmosphere, a pressure-equalizing dropping funnelcharged with the bromomethyl ketone 5 (2.5 g, 5.0 mmol) indichloromethane (40 mL) was attached to a 150-mL flask which contains asolution of methylamine (15 mL, 30 mmol, 1 M in THF). The flask wascooled to 0° C., and the bromide solution was added dropwise over 2hours. The resulting solution was stirred for one more hour, after whichtriethylamine (1 mL) and a solution of trimethylacetyl chloride (4.8 mL,40 mmol) in dichloromethane (10 mL) were added. The resulting mixturewas stirred for another 2 hours and then quenched with saturated sodiumbicarbonate solution. The mixture was extracted with ethyl acetate (3×50mL), and the combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Purification of the residue by flashchromatography (silica gel, ethyl acetate/hexane) provided ester 6 (1.3g, 49% overall), which was characterized by ¹H-NMR and LC/MS analysis(LRMS (M+H⁺) m/z: 535.35).

A solution of 6 (1.3 g, 2.6 mmol) in an excess of ammonium acetate informamide (10 mL) was heated to 130° C. under a nitrogen atmosphere for3 hours. The resulting mixture was cooled to room temperature,partitioned between water and extracted with dichloromethane (3×50 mL).The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, ethyl acetate/hexane) providing imidazole 7 (0.8 g, 60%),which was characterized by ¹H-NMR and LC/MS analysis (LRMS (M+H⁺) m/z:516.35).

A solution of 7 (800 mg, 1.55 mmol) in tetrahydrofuran (10 mL) wasstirred with hydrogen chloride in 1,4-dioxane (10 mL, 4.0 M) at roomtemperature for one hour. The solvents were removed in vacuo, and theresidue was dried under high vacuum overnight to yield intermediate 8(600 mg), which was determined to be pure enough for the nexttransformation (¹H-NMR and LC/MS (LRMS (M+H⁺) m/z 302.22)).

To a room temperature solution of amine 8 (60 mg, 0.02 mmol) indimethylformamide (3 mL) was added diisopropylethylamine (53 μL, 0.30mmol) and the resulting solution stirred at room temperature for 5minutes. Iintermediate 9 (23 mg, 0.06 mmol) was then added, and thereaction mixture was stirred under an atmosphere of nitrogen for 30minutes. The solvents were removed in vacuo, and the residue purified byflash chromatography (silica gel, methanol/dichloromethane) to provide10 (25 mg, 26%) as a glassy solid, which was characterized by ¹H NMR andLC/MS (LRMS (M+H⁺) m/z: 489.28).

Example 52

To a room temperature solution of 1 (4.96 g, 17 mmol) in methanol (15mL) was added dropwise a solution of TMS diazomethane in hexanes (17.0mL, 34 mmol, 2 M). The resulting yellow solution was stirred at ambienttemperature for 30 minutes. The solvents were removed in vacuo, and theviscous oil 2 (5.19 g, 17 mmol) was dried under high vacuum anddetermined to be pure enough for use in subsequent transformations.LC/MS (LRMS (M+H⁺) m/z: 305.3).

Intermediate 2 (5.19 g, 17 mmol) was stirred with sodium borohydride(3.23 g, 85 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) atroom temperature for 2 hours. The solvents were removed in vacuo, andthe residue was partitioned between ethyl acetate (50 mL) and water (50mL). The layers were separated and the aqueous phase was extracted withethyl acetate (3×50 mL), and the combined organic layers were dried oversodium sulfate and concentrated in vacuo to yield 3 (4.71 g, 17 mmol) asa white solid, which was determined to be pure enough for use insubsequent transformations LC/MS (LRMS (M+H⁺) m/z: 277.3). Nitrile 3(1.92 g, 6.9 mmol) was stirred with sodium methoxide in methanol (27.7mL, 13.9 mmol, 0.5 M) and hydroxylamine hydrochloride (964 mg, 13.9mmol) under an atmosphere of nitrogen at 50° C. for 2 hours. It was thencooled to room temperature and the solvents were removed in vacuo. Theresidue was partitioned between saturated aqueous ammonium chloridesolution (30 mL) and ethyl acetate (30 mL). The layers were separatedand the aqueous phase was extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo, and the residue was purified by flashchromatography (silica gel, hexane/ethyl acetate) to yield intermediate4 (1.08 g, 51%), which was characterized by ¹H NMR and LC/MS (LRMS(M+H⁺) m/z: 310.2).

To a room temperature solution of 4 (1.08 g, 3.5 mmol) in methanol (30mL) was added Raney nickel (200 mg) and acetic acid (1 mL). Theresulting mixture was stirred under an atmosphere of hydrogen at roomtemperature for 2 hours. It was filtered through Celite® andconcentrated in vacuo to provide 5 (1.02 g, 100%) as a white solid,which was determined to be pure enough for use in subsequenttransformations. LC/MS (LRMS (M+H⁺) m/z: 294.3).

To a room temperature solution of amidine 5 (304 mg, 1.0 mmol) inanhydrous ethanol (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene(622 μL, 4.2 mmol) and 3-bromo-1,1,1-trifluoro-2-butanone (424 mg, 2.1mmol). The resulting mixture was stirred under an atmosphere of nitrogenat 115° C. for 30 minutes. It was then cooled to room temperature andthe solvents removed in vacuo. The residue was purified by reverse-phaseHPLC using a mobile phase gradient consisting of acetonitrile and water.Compound 6 (76 mg, 20%) was isolated and characterized by ¹H NMR andLC/MS (LRMS (M+H⁺) m/z: 400.1).

A solution of 6 (76 mg, 0.2 mmol) in dichloromethane (2 mL) was stirredwith trifluoroacetic acid (2 mL) at room temperature for 45 minutes. Thesolvents were removed in vacuo to provide 7 (57 mg, 100%), which wasdetermined to be pure enough for use in subsequent transformations.LC/MS (LRMS (M+H⁺) m/z: 300.3).

To a room temperature solution of amine 7 (25 mg, 0.08 mmol) indimethylformamide (3 mL) was added diisopropylethylamine (87 μL, 0.50mmol). The resulting solution was stirred at room temperature for 5minutes and intermediate 8 (32 mg, 0.08 mmol) was added. The reactionmixture was stirred under an atmosphere of nitrogen at room temperaturefor 30 minutes, and the solvents were removed in vacuo. The residue waspartitioned between ethyl acetate (5 mL) and water (5 mL), after whichthe layers were separated and the aqueous phase was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, ethyl acetate) to provide 9 (7 mg, 18%) as aglassy solid, which was characterized by ¹H NMR and LC/MS (LRMS (M+H⁺)m/z: 496.4).

Example 53

To a room temperature solution of aniline 1 (500 mg, 1.3 mmol) indimethylformamide (3 mL) were added potassium carbonate (1.5 g) and1-bromopinacolone (500 mg, 2.8 mmol). The reaction mixture was stirredat 50° C. for 4 hours, and the solvents were removed in vacuo. Theresidue was partitioned between ethyl acetate (50 mL) and water (15 mL),the layers were separated, and the aqueous phase was extracted withethyl acetate (3×50 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash chromatography (silica gel, ethyl acetate) to provide 2 (320 mg,51%), which was characterized by ¹H NMR and LC/MS (LRMS (M+H⁺) m/z:479.74).

To a room temperature solution of 2 (307 mg, 0.64 mmol) in triethylorthoformate (20 mL) was added concentrated aqueous HCl (25 μL). Theresulting mixture was stirred at 90° C. for 3 hours and then cooled toroom temperature. The solvents were removed in vacuo and the residuepartitioned between water (15 mL) and ethyl acetate (50 mL). The layerswere separated and the organic layer washed with water (3×20 mL) andbrine (3×20 mL), and dried over sodium sulfate. Removal of the solventsyielded intermediate 3 (326 mg, 100%) as a viscous oil, which wascharacterized by LC/MS (LRMS (M+H⁺) m/z: 507.1).

Intermediate 3 (207 mg, 0.41 mmol) was stirred with ammonium acetate(1.57 g, 20.40 mmol) in formamide under an atmosphere of nitrogen at130° C. for 4.5 hours. The resulting solution was cooled to roomtemperature and partitioned between ethyl acetate (50 mL) and water (10mL). The layers were separated, the organic layer was washed with water(4×10 mL) and brine (20 mL) and dried over sodium sulfate. The solventswere removed in vacuo, and the residue was purified by reverse-phaseHPLC using a mobile phase gradient consisting of acetonitrile and waterto yield imidazole 4 (159 mg, 80%), which was isolated and characterizedby ¹H NMR and LC/MS (LRMS (M+H⁺) m/z: 488.2).

To a room temperature solution of 4 (159 mg, 0.33 mmol) indichloromethane (4 mL) was added trifluoroacetic acid (4 mL), and theresulting solution stirred at room temperature overnight. The solventswere removed in vacuo provide amine 5 (89 mg) as a glassy solid, whichwas determined to be pure enough for use in subsequent transformationsLC/MS (LRMS (M+H⁺) m/z: 274.1).

Crude amine 5 (72 mg, 0.26 mmol) was stirred with diisopropylethylamine(197 μL, 1.1 mmol) in dimethylformamide (3 mL) at room temperature for 5minutes, after which intermediate 6 (100 mg, 0.26 mmol) was added. Theresulting mixture was stirred for another 30 minutes and the solventsremoved in vacuo. The crude residue was purified by reverse-phase HPLCusing a mobile phase gradient consisting of acetonitrile and water togive compound 7 (10 mg, 8%) as a glassy solid, which was characterizedby ¹H NMR and LC/MS (LRMS (M+H⁺) m/z: 470.2).

To a room temperature solution of alcohol 1 (2.59 g, 9.4 mmol) inbenzene (50 mL) was added 2,2-dimethoxypropane (1.75 mL, 14.1 mmol) andp-toluenesulfonic acid (179 mg, 0.94 mmol). The resulting solution wasstirred under an atmosphere of nitrogen at 110° C. for 1.5 hours. Thesolvents were removed in vacuo, and the residue purified using flashchromatography (silica gel, ethyl acetate/hexanes) to provide 2 (765 mg,27%), which was characterized using LC/MS (LRMS (M+H⁺) m/z: 317.4).

Nitrile 2 (765 mg, 2.4 mmol) was stirred with sodium methoxide inmethanol (10.0 mL, 5.0 mmol, 0.5 M) and hydroxylamine hydrochloride (336mg, 4.8 mmol) under an atmosphere of nitrogen at 50° C. for 2 hours. Itwas then cooled to room temperature and the solvents removed in vacuo.The residue was partitioned between saturated aqueous ammonium chloridesolution (30 mL) and ethyl acetate (30 mL), the layers were separated,and the aqueous phase extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, hexane/ethyl acetate) to yield intermediate 3 (314 mg,38%), which was characterized by ¹H NMR and LC/MS (LRMS (M+H⁺) m/z:350.1).

To a room temperature solution of 3 (314 mg, 0.9 mmol) in methanol (15mL) was added Raney nickel (50 mg) and acetic acid (300 μL). Theresulting mixture was stirred under an atmosphere of hydrogen at roomtemperature for 2 hours. It was filtered through Celite® andconcentrated in vacuo to provide 4 (275 mg, 0.83 mmol) as a white solid,which was determined to be pure enough for use in subsequenttransformations. LC/MS (LRMS (M+H⁺) m/z: 414.1).

To a room temperature solution of amidine 4 (138 mg, 0.4 mmol) inanhydrous ethanol (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene(622 μL, 4.2 mmol) and 1-bromopinacolone (84 μL, 0.6 mmol). Theresulting mixture was stirred under an atmosphere of nitrogen at 115° C.for 30 minutes. It was then cooled to room temperature and the solventsremoved in vacuo. The residue was purified by reverse-phase HPLC using amobile phase gradient consisting of acetonitrile and water to givecompound 5 (29 mg, 17%), which was characterized using ¹H NMR and LC/MS(LRMS (M+H⁺) m/z: 414.1).

To a room temperature solution of imidazole 5 (29 mg, 0.07 mmol) inanhydrous dimethylformamide (5 mL) were added potassium carbonate (39mg, 0.28 mmol) and dimethylsulfate (133 μL, 1.40 mmol). The resultingmixture was stirred under an atmosphere of nitrogen at 50° C. for 24hours, after which the solvents were removed in vacuo. The residue waspurified using flash chromatography (silica gel, ethyl acetate/hexanes)to provide 6 (15 mg, 43%) as a glassy solid, which was characterized by¹H NMR and LC/MS (LRMS (M+H⁺) m/z: 428.3).

A solution of 6 (15 mg, 0.04 mmol) in anhydrous methanol (3 mL) andwater (300 μL) was stirred with DOWEX 50WX8-400 ion-exchange resin (100mg) at room temperature for 16 hours. The resin was removed byfiltration and rinsed with triethylamine (3 mL). The solvents wereremoved under high vacuum to provide 7 (12 mg, 0.04 mmol), which wasdetermined to be sufficiently pure for the next transformation. LRMS(M+H⁺) m/z: 288.2.

To a room temperature solution of amine 7 (12 mg, 0.04 mmol) indimethylformamide (3 mL) was added diisopropylethylamine (20 μL, 0.10mmol). The resulting solution was stirred at room temperature for 5minutes, after which intermediate 8 (16 mg, 0.04 mmol) was added. Thereaction mixture was stirred for another 30 minutes. The solvents wereremoved in vacuo and the residue purified by flash chromatography(silica gel, methanol/dichloromethane) to provide 9 (10 mg, 50%) as aglassy solid, which was characterized by ¹H NMR and LC/MS (LRMS (M+H⁺)m/z: 484.2).

To a solution of Boc-L-β-homotyrosine(OBzl) (5 g, 13 mmol) in methanol(200 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 40 mL, 78mmol) dropwise. The reagent was continuously added if necessary untilbubbling ceased. The mixture was concentrated to give 2 (5.5 g), whichwas used in the next step without further purification. LRMS (M+H⁺) m/z300.3.

To a solution of 2 (5.5 g, 13.76 mmol) in THF (100 mL) was added LAH (1M in THF, 13.7 mL, 13.7 mmol) at 0° C. The resulting solution wasstirred for 2 hours, after which methanol (˜20 mL) was added to quenchthe reaction. The solvents were evaporated to obtain the yellowish solidwhich was diluted in ethyl acetate and washed in saturated NaHCO₃. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified via flash columnchromatography using a mixture of ethyl acetate and hexanes as eluent togive 3 as a white solid (3.5 g, 70%). LRMS (M+H⁺) m/z 394.4.

A solution of 3 (1.9 g, 5 mmol) in MeOH (40 mL) was stirred under astream of H₂ (50 psi) in the presence of 10% Pd/C (200 mg) for 30 h. Thecatalyst was removed by filtration through a PTFE (0.45 μm) filter andthe solvent evaporated to give a white solid (1.5 g), which was stirredin the mixture of TFA (1 mL) and dichloromethane (9 mL) for 2 hours. Theresulting solution was concentrated and used in the next step withoutfurther purification. LRMS (M+H⁺) m/z 182.3.

To a solution of 4 (926 mg, 5 mmol) in THF (10 mL) were added 5 (950 mg,2.6 mmol) and N,N-diisopropylethylamine (4.5 mL, 25.5 mmol). Thereaction was stirred at room temperature for 10 hours. The mixture wasconcentrated and dried on high vacuum. The resulting crude product waspurified via flash column chromatography using ethyl acetate as eluentto give 6 (710 mg, 74%). LRMS (M+H⁺) m/z 370.4.

To a solution of 6 (70 mg, 0.2 mmol) in DMF (1 mL) was added4-fluorobenzyl bromide (0.15 mL, 1.2 mmol) and potassium carbonate (166mg, 1.2 mmol). The resulting mixture was stirred for 12 hours at roomtemperature. The mixture was filtered, and the filtrate was purified byRP-HPLC using a mixture of acetonitrile and H₂O to give 1e (35 mg, 37%).LRMS (M+H⁺) m/z 477.5.

A solution of imidate 15 (20 mg, 0.05 mmol), pivalic acid hydrazide (9mg, 0.08 mmol), and acetic acid (1 mL) was stirred at 80° C. for 1 hr.The reaction mixture was then concentrated in vacuo and the resultingresidue purified by reverse phase HPLC (C18, acetonitrile/water) toyield 10 mg (43%) of the tetrazole 16. LRMS (M+H⁺) m/z 471.2.

A solution of pentafluorophenyl ester 28 (1.0 g, 2.62 mmol), amine 29(0.49 mL, 3.15 mmol), and THF (10 mL) was stirred at 23° C. for 4 hours.The reaction solution was concentrated in vacuo, and the resultingresidue was purified by column chromatography (silica gel, 1:1EtOAc:hexanes) to give 1.1 g (88%) of amide 30. LRMS (M+H⁺) m/z 396.1.

A solution of bromide 30 (200 mg, 0.51 mol),dichlorobis(triphenylphosphine) palladium(II) (35 mg, 0.05 mol),tributyl(1-ethoxyvinyl)tin (0.34 mL, 1.0 mmol), and toluene (2 mL) underN₂ was stirred at 100° C. for 4 hours. Upon completion, as monitored byLCMS, the reaction mixture was cooled, filtered through cotton, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:4:0.1 EtOAc: hexanes:triethylamine) to give 100 mg (52%) of styrene 31. LRMS (M+H⁺) m/z388.2.

A solution of compound 31 (100 mg, 0.25.mmol), THF:H₂O (3:1, 4 mL), andN-bromo-succinimide (46 mg, 0.25 mmol) was stirred at 23° C. for 15 min.The reaction mixture was then concentrated in vacuo, and the cruderesidue was diluted with EtOAc (30 mL), washed with brine (10 mL), andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 4:1 EtOAc:hexanes) to give 50 mg(46%) of bromoketone 32. LRMS (M+H⁺) m/z 438.1.

A solution of bromoketone 32 (50 mg, 0.11 mmol), K₂CO₃ (47 mg 0.34mmol), tert-butylcarbamidine hydrochloride (21 mg, 0.23 mmol), and DMF(2 mL) was stirred at 23° C. under N₂ for 18 hours. The reaction mixturewas concentrated in vacuo under high vacuum (0.1 mm Hg), and theresulting residue was purified by column chromatography (silica gel, 2:1EtOAc:hexanes) to give 35 mg (72%) of imidazole 34. LRMS (M+H⁺) m/z440.2.

Chloroform (20 mL) was added slowly over 2 hours to a solution ofBoc-tyrosine (20 g, 71 mmol) and 10% NaOH in H₂O (400 mL) at 85° C.After a total of 4 hours, the reaction solution was acidified with 3 NHCl (200 mL) and extracted with EtOAc (3×150 mL). The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by flash column chromatography (silica gel, 1:1:0.1hexanes:EtOAc:AcOH) to yield 6.3 g of a mixture of aldehyde 35 and somerecovered 34.

A solution of aldehyde 35 (contaminated with 34, 6.3 g, 20 mmol), K₂CO₃(5.8 g, 42 mmol), benzyl bromide (5.0 mL, 42 mmol), and DMF (100 mL) wasstirred at 23° C. for 18 hours. The reaction mixture was diluted withEtOAc (200 mL), and washed with 1 N HCL (3×200 mL) and brine (3×200 mL).The organic layer was dried (MgSO₄), filtered, and concentrated invacuo. The resulting residue was purified by column chromatography(silica gel, 1:4 EtOAc:hexanes) to give 2.2 g (22%) of ester 36. LRMS(M+H⁺) m/z 490.2.

A solution of aldyhyde 36 (570 mg, 1.16 mmol), KMnO₄ (368 mg, 2.32mmol), dioxane (3 mL), and H₂O (1 mL) was stirred at 23° C. for 3 hours.The reaction mixture was concentrated in vacuo and the resulting residuewas purified by column chromatography (silica gel, 1:1 EtOAc:hexanes) togive 350 mg (60%) of acid 37. LRMS (M+H⁺) m/z 506.2.

A solution of acid 37 (115 mg, 0.23 mmol), dimethyl amine (0.23 mL, 2.0M in THF), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(65 mg, 0.34 mmol), diisopropyl ethyl amine (0.12 mL, 0.68 mmol), andCH₂Cl₂ (1 mL) was stirred at 23° C. for 4 hours. The reaction mixturewas then diluted with EtOAc (10 mL), and washed with 1 N HCl (5 mL) andbrine (5 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:1 hexanes:EtOAc) to yield 60 mg(49%) of amide 38. LRMS (M+H⁺) m/z 533.3.

A solution of amide 38 (60 mg, 0.11 mmol), TFA:H₂O (97.5:2.5, 1 mL) andCH₂Cl₂ (1 mL) was stirred at 23° C. for 30 min. The reaction solutionwas concentrated in vacuo, and the resulting residue was placed underhigh vacuum for 2 hours and then used without further purification.

A solution of crude amine 39 (69 mg, 0.16 mmol), pentafluorophenol ester40 (71 mg, 0.19 mmol), diisopropylethylamine (83 μL, 0.68 mmol), and DMF(1 mL) was stirred at 23° C. for 4 hours. The reaction mixture was thendiluted with EtOAc (10 mL), and washed with 1 N HCl (5 mL) and brine (5mL). The organic layer was dried (MgSO₄), filtered, and concentrated invacuo. The resulting residue was purified by flash column chromatography(silica gel, 1:1 hexanes:EtOAc) to yield 60 mg (60%) of the ester amide41. LRMS (M+H⁺) m/z 620.3.

A solution of ester 41 (50 mg, 0.08 mmol), NaBH₄ (30 mg, 0.81 mmol), THF(0.5 mL), and MeOH (0.5 mL) was stirred at 23° C. for 2 hours. Thereaction mixture was then diluted with EtOAc (10 mL), and washed with 1N HCl (5 mL) and brine (5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography (silica gel, 1:50 MeOH:EtOAc) to yield 31mg (75%) of the alcohol 42. LRMS (M+H⁺) m/z 516.3.

A solution of acid 43 (300 mg, 1.0 mmol), K₂CO₃ (276 mg, 2.0 mmol),benzyl bromide (0.24 mL, 2.0 mmol), and DMF (4 mL) was stirred at 23° C.for 18 hours. The reaction mixture was diluted with EtOAc (30 mL), andwashed with 1 N HCl (10 mL) and brine (3×15 mL). The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by column chromatography (silica gel, 1:3EtOAc:hexanes) to give 400 mg (83%) of ester 44. LRMS (M+H⁺) m/z 480.2.

A solution of ester 44 (100 mg, 0.21 mmol), NaBH₄ (24 mg, 0.63 mmol),THF (1 mL), and MeOH (1 mL) was stirred at 23° C. for 18 hours. Thereaction mixture was then diluted with EtOAc (10 mL), washed with 1 NHCl (5 mL), and brine (5 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting residue was usedwithout further purification.

A solution of alcohol 45 (100 mg, 0.27 mmol) and TFA:H₂0 (97.5:2.5, 1mL) was stirred at 23° C. for 30 min. The reaction solution wasconcentrated in vacuo, and the resulting residue was placed under highvacuum for 2 hours and then used without further purification.

A solution of amine 46 (40 mg, 0.15 mmol), pentafluorophenyl ester 40(43 mg, 0.12 mmol), triethylamine (51 μL, 0.29 mmol), and DMF (0.6 mL)was stirred at 23° C. for 4 hours. The reaction mixture was then dilutedwith EtOAc (10 mL), and washed with 1 N HCl (5 mL) and brine (5 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by flash column chromatography(silica gel, 1:2 hexanes:EtOAc) to yield 30 mg (43%) of the ester amide47. LRMS (M+H⁺) m/z 463.2.

A solution of aldehyde 36 (300 mg, 0.6 mmol), dimethyl hydrazine (47 μL,0.6 mmol), and MeOH (2.5 mL) was stirred at 0° C. for 2 hours, thenallowed to warm to 23° C. and stirred for an additional 15 hours. Thereaction solution was concentrated in vacuo and the resulting residuewas used without further purification.

To a −5° C. solution of crude hydrazone 48 (325 mg, 0.6 mmol) and CHCl₃(2 mL) was added dropwise a solution of m-chloroperoxybenzoic acid (212mg, 1.23 mmol) and CHCl₃ (2 mL). The reaction solution was allowed towarm to 23° C. and was stirred for 2 days. The reaction mixture was thendiluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO₃ (5mL) and brine (5 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:2 hexanes:EtOAc) to yield 100 mg(34%) of the nitrile 49. LRMS (M+H⁺) m/z 487.2.

A solution of nitrile 49 (60 mg, 0.27 mmol) and TFA:H₂O (97.5:2.5, 2 mL)was stirred at 23° C. for 30 min. The reaction solution was concentratedin vacuo, and the resulting residue was placed under high vacuum for 2hours and then used without further purification.

A solution of amine 50 (100 mg, 0.25 mmol), pentafluorophenyl ester 40(85 mg, 0.22 mmol), triethylamine (96 μL, 0.74 mmol), and DMF (1 mL) wasstirred at 23° C. for 4 hours. The reaction mixture then diluted withEtOAc (10 mL), and washed with 1 N HCl (5 mL) and brine (5 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by flash column chromatography(silica gel, 1:1 hexanes:EtOAc) to yield 60 mg (42%) of 51. LRMS (M+H⁺)m/z 574.2.

A solution of ester 51 (60 mg, 0.1 mmol), NaBH₄ (12 mg, 0.3 mmol), THF(1 mL), and MeOH (1 mL) was maintained at 23° C. for 18 hrs. Thereaction mixture then diluted with EtOAc (10 mL), washed with 1 N HCl (5mL), and brine (5 mL). The organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:2 hexanes:EtOAc) to yield 30 mg(64%) of the alcohol 52. LRMS (M+H⁺) m/z 470.2.

A solution of amide 55 (1.6 g, 4.38 mmol) and diethylaniline 56 (5 mL)was maintained at 240° C. for 18 hrs. The reaction solution was cooledto 23° C., diluted with EtOAc (30 mL), and washed with 1 N HCl (3×50 mL)and brine (2×50 mL). The organic layer was dried (MgSO₄), filtered, andthe filtrate was concentrated in vacuo. The resulting residue waspurified by flash column chromatography (silica gel, 2:1 hexanes:EtOAc)to yield 1 g (63%) of phenol 56. LRMS (M+H⁺) m/z 365.2.

A solution of phenol 56 (700 mg, 1.92 mmol), Cs₂CO₃ (1.25 mg, 3.84mmol), benzyl bromide (0.46 mL, 3.84 mmol), and DMF (10 mL) wasmaintained at 50° C. for 2 hrs. The reaction mixture was diluted withEtOAc (30 mL), washed with 1 N HCL (20 mL) and brine (3×30 mL). Theorganic layer was dried (MgSO₄), filtered, and the filtrate wasconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (silica gel, 1:3 EtOAc:hexanes) to give 500 mg(57%) of amide 57. LRMS (M+H⁺) m/z 455.2.

A solution of amide 57 (150 mg, 0.33 mmol), osmium tetroxide (8 mg, 0.03mmol), N-methylmorpholine-N-oxide (182 mg, 1.55 mmol), pyridine (2.4 [L,0.03 mmol), THF (2 mL) and H₂O (2 mL) was maintained at 23° C. After 2hrs, Celite® (1 g), NaHSO₃ (1 g) and EtOAc (20 mL) were added and theresulting mixture was stirred. After 30 min, the reaction mixture wasfiltered and the resulting filtrate was concentrated in vacuo. Theresulting residue was purified by flach column chromatography (silicagel, 3:1 EtOAc:hexanes) to give 100 mg (62%) of diol 58. LRMS (M+H⁺) m/z489.2.

A solution of diol 58 (52 mg, 0.11 mmol), Pb(OAc)₄, and CH₂Cl₂ (2 mL)was maintained at 23° C. for 30 min. The reaction mixture was thenfiltered through a plug of Celite® and the filtrate was concentrated toprovide the aldehyde as a colorless oil.

A solution of the crude aldehyde (˜50 mg, ˜0.11 mmol), NaBH₄ (24 mg,0.63 mmol), THF (1 mL), and MeOH (1 mL) was maintained at 23° C. for 30min. The reaction mixture then diluted with EtOAc (10 mL), washed with 1N HCl (5 mL), and brine (5 mL). The organic layer was dried (MgSO₄),filtered, and the filtrate was concentrated in vacuo. The resultingresidue was purified by flash column chromatography (silica gel, 2:1EtOAc:hexanes) to give 20 mg (40%) of alcohol 59. LRMS (M+H⁺) m/z 459.2.

A solution of styrene 60 (190 mg, 0.54 mmol), borane-THF (1.0 M, 0.54mL) was maintained at 23° C. for 2 hrs. An additional amount ofborane-THF (0.54 mL) was then added. After another 2 hrs, an thirdportion (0.54 mL) was added. The reaction solution was maintained for 18hrs, cooled to 0° C., then 3 N NaOH (0.5 mL) and H₂O₂ (0.5 mL) wasadded. After 2 hrs at 23° C., the reaction mixture was diluted withEtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried(MgSO₄), filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified by flash column chromatography (silicagel, 2:1 EtOAc:hexanes) to give 150 mg (75%) of alcohol 61. LRMS (M+H⁺)m/z 372.2.

A solution of alcohol 61 (120 mg, 0.32 mmol), TFA:H₂O (97.5:2.5, 4 mL)was maintained at 23° C. for 30 min. The reaction solution wasconcentrated in vacuo, and the resulting residue was placed under highvacuum for 2 hours and then used without farther purification.

A solution of the above amine 62 (50 mg, 0.18 mmol), pentafluorophenolester 40 (82 mg, 0.22 mmol), triethylamine (96 μL, 0.55 mmol), and DMF(1 mL) was maintained at 23° C. for 2 hrs. The reaction mixture thendiluted with EtOAc (10 mL), washed with 1 N HCl (5 mL), and brine (5mL). The organic layer was dried (MgSO₄), filtered, and the filtrate wasconcentrated in vacuo. The resulting residue was purified by reversephase HPLC (C18, acetonitrile/water) to yield 6 mg (7%) of the amide 63.LRMS (M+H⁺) m/z 459.2.

To a solution of 10 (1.15 g, 2.71 mmol) in dichloromethane (100 mL) wasadded Dess-Martin periodinane (2.30 g, 5.42 mmol). The reaction mixturewas stirred for 1 h, after which the dichloromethane solution was washedby sodium thiosulfate solution and sodium bicarbonate solution, anddried over sodium sulfate. The mixture was filtered and the filtrateconcentrated under reduced pressure to give 23 (1.0 g, 87%).

To a solution of 23 (30.0 mg, 0.0711 mmol) in dichloromethane (2 mL)were added diisopropylethylamine (37.0 uL, 0.213 mmol), 24 (12.9 uL,0.213 mmol) and sodium triacetoxyborohydride (20.0 mg, 0.142 mmol). Thereaction mixture was stirred overnight, and then concentrated underreduced pressure. The residue was purified by reverse phase HPLC (C18)using a mixture of acetonitrile and H₂O to give 25 (5.6 mg, 16.9%). LRMS(M+H⁺) m/z 467.4.

To a solution of 23 (50.0 mg, 0.119 mmol) in methanol (2 mL) were addeddiisopropylethylamine (62.0 uL, 0.356 mmol), 26 (31.1 uL, 0.356 mmol)and sodium cyanoborohydride (22.4 mg, 0.356 mmol). The reaction mixturewas stirred for overnight, then concentrated under reduced pressure andthe residue purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 27 (31.0 mg, 22.9%). LRMS (M+H⁺) m/z 518.5.

To a solution of 1 (1.0 g, 4.66 mmol) in MeOH (10.0 mL) was added SOCl₂(0.68 mL, 9.32 mmol). After stirring overnight at ambient temperature,the solution was concentrated in vacuo and taken on withoutpurification.

To a solution of 2 (˜1.065 g crude, 4.66 mmol) in EtOH (1.5 mL) wasadded N₂H₄.H₂O (1.13 mL, 23.3 mmol). The reaction mixture was heated toreflux and stirred for 3 h. Upon cooling, the solution was treated withH₂O, extracted with trice with EtOAc, dried over MgSO₄, filtered, andconcentrated. Recrystallization from CH₂Cl₂ yielded 1.01 g 3 as whitecrystals; 95% yield, 2 steps.

To a solution of 3 (0.477 g, 2.09 mmol) in THF (8.0 mL) was addedcarbonyldiimidazole (0.379 g, 2.29 mmol). The reaction mixture washeated to reflux and stirred for 1.5 h. Upon cooling, the solution wasconcentrated in vacuo and purified via flash column chromatography(10-40% EtOAc/Hex) to yield 0.515 g 4 (97%) as a white solid.

To a solution of 4 (1.0 equiv.; typically 0.3-1.0 mmol) in CH₃CN (2.0mL) was added the electrophile (1.1 equiv.) and K₂CO₃ (1.1 equiv.). Thereaction mixture was heated to 80° C. under microwave irradiation for 30min followed by filtration and concentration in vacuo. The product canbe taken on without purification or purified via flash columnchromatography (typically 10-40% EtOAc/Hex) to afford 5 ingenerally >90% yield.

To 5 (1.0 equiv.; typically 0.3-1.0 mmol) was added methylamine (2.0 Msolution in THF, 10.0 equiv.). The reaction mixture was heated to 100°C. under microwave irradiation for 4 h followed by concentration invacuo. The product was purified via flash column chromatography(typically 40-80% EtOAc/Hex) to afford 6 in generally 70-85% yield.

To a stirred solution of 2-aminoacetonitrile bisulfate (2.9 g, 0.013mmol) in dichloromethane (50 mL) was added benzophenone (3.48 mL, 0.0208mmol) followed by DIEA (4.53 mL, 0.026 mmol). After stirring 18 h, thedichloromethane solution was washed with water (50 mL), dried oversodium sulfate, filtered, and the filtrate concentrated under reducedpressure. The residue was purified on a flash silica gel column(hexanes:EtOAc, 1:1) to give 3 (2.40 g, 82%).

Lithium bis(trimethylsilyl)amide (1 M solution in THF) was slowly addedto a stirred solution of 3 (1.2 g, 0.00545 mol) and p-phenylbenzylbromide (1.08 g, 0.00436 mol) in THF (50 mL) over an acetone-dry icebath under a nitrogen atmosphere. After 1 hour, the reaction wasquenched by adding methanol, and the solvent was evaporated underreduced pressure. The residue was purified on a flash silica gel column(hexanes:EtOAc, 1:1) to obtain 4. 4 was re-suspended in EtOAc (100 mL)and treated with concentrated HCl (5 mL). After stirring for 1 hour, thesolvents were evaporated under reduced pressure, and the resulting solid5 was washed with ethyl ether (50 mL) three times and dried under vacuum(0.39 g, 32.1%).

To a solution of 5 (0.39 g, 1.75 mmol) in DMF (10 mL) were added 6(0.801 g, 2.11 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol) atroom temperature. The reaction mixture was stirred overnight. Thesolvents were then evaporated under reduced pressure, and the residuepurified on a flash silica gel column (hexane:EtOAc, 3:1) to give 7(0.40 g, 54.5% ). LCMS (M+H⁺) m/z 419.1.

To a solution of 7 (50 mg, 0.119 mmol) in DMF (2 mL) were added sodiumazide (15.5 mg, 0.239 mmol) and ammonium chloride (12.8 mg, 0.238 mmol).The mixture was stirred at 80° C. overnight and then filtered. Thefiltrate was purified by reverse phase HPLC (C18) using a mixture ofacetonitrile and H₂O to give 8 (6.40 mg, 11.6%). LCMS (M+H⁺) m/z 462.4.

To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J.Med. Chem, 2002, 45, 5769) in dimethylformamide (800 mL) was added2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4mol). The resulting mixture was heated at 50° C. for 16 h, at which timeit was allowed to cool to room temperature. The reaction was filteredand the mother liquor diluted with 0.5 N sodium hydroxide (1 L). Theresulting mixture was extracted with ether (2×1 L) and the organicswashed with 1 N HCl (1 L) and brine (700 mL), dried (MgSO₄) andconcentrated to give 100 g (˜100%) of methyl3-cyano-4-[(1-methylethyl)oxy]benzoate as a yellow solid.

To a cooled (0° C.) solution of methyl3-cyano-4-[(1-methylethyl)oxy]benzoate (100 g, 463 mmol) intetrahydrofuran (500 mL) was added 10% potassium hydroxide (500 mL). Theresulting solution was allowed to warm to room temperature andmaintained for 16 h, at which time it was concentrated to remove thetetrahydrofuran. The residue was diluted with water (500 mL) and washedwith ether (2×500 mL). The aqueous layer was then acidified with 3 N HCland stood for 2 h. The solids were collected by filtration and washedseveral times with water, then dissolved in methylene chloride (1 L).The mostly homogeneous mixture was filtered through Celite® andconcentrated to a minimal volume of methylene chloride. Collection ofthe solids by filtration gave 82 g (87%) of3-cyano-4-[(1-methylethyl)oxy]benzoic acid as a white solid.

Reagents and Conditions: a) 4N HCl/dioxane, rt; b) HBTU, i-Pr₂NEt, DMF,rt; c) 1-ethoxyvinyltri-n-butyltin, PdCl₂(PPh₃)₂, dioxane, 100° C.; d)NBS, THF/H₂O (3:1), rt; e) 2-amino-3-picoline, NaHCO₃, i-PrOH, 80° C.

(3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride

1,1-Dimethylethyl{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (4.4 g, 12.8mmol) was dissolved in 4N HCl/dioxane (20 mL). After 2 h, the reactionmixture was concentrated in vacuo to give 3.69 g (94%) of the titlecompound as a white solid. LC/MS (ES) m/e 244.0 (M+H)⁺.

N-{(1S)-1-[(4-Bromophenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide.

To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanolhydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was addedN,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clearsolution was stirred for 3 min. 3-Cyano-4-[(1-methylethyl)oxy]benzoicacid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and thereaction was stirred at rt under nitrogen. After 1.5 h, the reactionmixture was quenched with water (50 mL) and extracted with EtOAc (3×30mL). The extracts were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as awhite solid. LC/MS (ES) m/e 431.2 (M+H)⁺.

N-((1S)-1-{[4-(Bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

A flask, dried with a heat gun under argon purge, was charged withN-{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide(1.0 g, 2.32 mol), dichlorobis(triphenylphosphine)-palladium(II) (81 mg,0.116 mol), tributyl(1-ethoxyvinyl)tin (1.68 g, 4.64 mmol), and1,4-dioxane (15 mL). The mixture was stirred at 100° C. for 2 hoursunder argon. Upon completion, as monitored by LCMS, the reaction wasconcentrated under reduced pressure and the residue was purifiedimmediately on deactivated silica gel (65% EtOAc/hexanes with 5%triethylamine) to give 720 mg (1.70 mmol) of enol ether intermediate asa colorless foam which was immediately dissolved in THF:H₂O (3:1, 18 mL)and treated with N-bromosuccinimide (318 mg, 1.79 mmol). After 15 min atrt, the reaction mixture was concentrated under reduced pressure and thecrude residue was diluted with EtOAc (30 mL), washed with brine (10 mL)and water (10 mL) and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (80% EtOAc/hexanes) to give651 mg (59%) ofN-((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamideas a white tacky solid. LC/MS (ES) m/e 473.2 (M+H)⁺.

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

To a solution ofN-((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide(300 mg, 0.634 mmol) in i-PrOH (6 mL) was added 2-amino-3-picoline(Aldrich, 69 mg, 0.634 mmol) followed by solid NaHCO₃ (64 mg, 0.761mmol). The resultant suspension was heated to 80° C. After 7 h, amajority of the i-PrOH was removed under reduced pressure and theresidue was dissolved in 3% MeOH/EtOAc (30 mL) and washed with water (10mL) and brine (10 mL). The combined aqueous layers were extracted with3% MeOH/EtOAc (30 mL) and the combined extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC (MeCN/H₂O with 0.1% TFA) and the cleanfractions were adjusted to pH ˜8 with saturated aqueous NaHCO₃ andextracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure to give 215mg (70%) of the title compound as a pale yellow solid. LC/MS (ES) m/e483.2 (M +H)⁺.

1-(2-amino-3-pyridinyl)ethanol

To a dry flask (dried with a heat gun under argon purge) was added dryTHF (400 mL) and MeLi—LiBr (137 mL of a 1.5 M solution in Et₂O, 204.9mmol) via cannula. This solution was cooled to −78° C. when a solutionof 2-aminopyridine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL)was added dropwise via a pressure equalizing addition funnel over ˜45min with vigorous stirring (exotherm observed, orange color persisted).Upon complete addition, the solution was allowed to stir for 1 hour at−78° C., at which time TLC (KMnO₄ stain with heat) indicated that mostof the starting material had been converted to product. The reaction wasquenched very carefully with water (200 mL; dropwise initially), dilutedwith EtOAc (200 mL) and allowed to warm to rt. The layers were separatedand the aqueous layer was extracted with 3% MeOH in EtOAc. The combinedextracts were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desiredracemic product as a yellow oil that solidified under high vac overseveral days. This material was separated into its respectiveenantiomers (>98% ee) by SFC with a chiralcel OD-H (20×250 mm) column(10% EtOH/0.1% isopropylamine in heptane/0.1% isopropylamine).

1,1-Dimethylethyl[(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate

To a solution of 1,1-dimethylethyl{(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (20 g, 58mmol) in dioxane (500 mL) was addedtributyl[1-(ethyloxy)ethenyl]stannane (39 mL, 116 mmol) andPdCl₂(PPh₃)₂. The resulting solution was heated at 100° C. for 5 h. Thereaction was then concentrated and the residue purified by flashchromatography (47.5% EtOAc, 47.5% hexanes, 5% triethylamine) to give 15g (77%) of 1,1-dimethylethyl[(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamateas a brown solid.

1,1-Dimethylethyl((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate

To a cooled (0° C.) solution of 1,1-dimethylethyl[(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate(15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was addedN-bromosuccinamide. The resulting solution was allowed to warm to roomtemperature and maintained for 90 minutes. The reaction was thenconcentrated and diluted with ethyl acetate (1 L). The resultingsolution was washed with water (1 L) and brine (500 mL), dried (MgSO₄)and concentrated to give 19.5 g (˜100%) of1,1-dimethylethyl((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamateas a slightly yellow solid. ESMS [M+H]⁺: 386.2.

1,1-Dimethylethyl[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate

A mixture of1,1-dimethylethyl((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate(1.00 g, 2.59 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.358 g, 2.59mmol), and solid sodium bicarbonate (0.272 g, 3.24 mmol) in isopropanol(25 mL) was heated at reflux for 3.5 h. and concentrated in vacuo. Theresidue was dissolved in ethyl acetate, washed with water and brine,dried (Na₂SO₄), and concentrated. The resulting pale yellow solid wasused in the next reaction without further purification. MS(ES+) m/e 426[M+H]⁺.

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of1,1-dimethylethyl[(1S)-3-hydroxy-1-({4-[-8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]carbamate(1.08 g, 2.54 mmol) and 4M HCl in 1,4-dioxane (8.0 mL, 32 mmol) wasstirred at room temperature for 30 minutes. The reaction wasconcentrated to dryness, redissolved in DMF (25 mL), and to thissolution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) andpentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (0.963 g, 2.54mmol). The mixture was stirred for 3.0 h at room temperature, dilutedwith water, and extracted into ethyl acetate. The extracts were washedwith water and saturated sodium chloride, dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) asa pale yellow powder. MS(ES+) m/e 522 [M+H]⁺.

1,1-Dimethylethyl[(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate

To a solution of4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowlylithium aluminum hydride, 95% (108.9 mmol). The resulting solution wasstirred for an additional 2 h at 0° C. The reaction was then carefullyquenched with a saturated aqueous solution of sodium bicarbonate (73 mL)which stirred at RT for half an hour. Lithium aluminium salts crashedout of solution and were removed by filtration. The filtrate wasconcentrated and vacuum pumped for 24 h to afford the title product as awhite solid (97%). ESMS [M+H]⁺: 331.2.

1,1-Dimethylethyl{(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

To a solution of1,1-dimethylethyl[(1s)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate(70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol)in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwisediisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reactioncontinued to stir allowing to warm to RT over 5h. The reaction was thenconcentrated in vacuo and product was triturated out of solution usingethyl acetate (500 mL). The precipitate was filtered, washed with ethylacetate (3×100 mL), and dried to afford the title product as a whitesolid (57%). ESMS [M+H]⁺: 460.4.

1,1-Dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

A solution of1,1-dimethylethyl{(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate(21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), andtrans-dichlorobis(triphenylphospine)palladium(II) (5 mol %) were stirredin anhydrous dioxane (300 mL) at 100° C. for 3 h. The reaction was thenconcentrated in vacuo and redissolved in a solution of tetrahydrofuranand water (3:1, 400 mL). The mixture was treated with N-bromosuccinimide(108.8 mmol) and stirred at RT for half an hour. The reaction solutionwas then concentrated to dryness and redissolved in ethyl acetate (150mL). Precipate formed upon addition of hexanes (350 mL) and was filteredand dried to afford the title product as yellow solid (71%). ESMS[M+H]⁺: 502.4.

1,1-Dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate

A mixture of1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate(1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol(24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuoand the residue dissolved in ethyl acetate, washed with water andsaturated sodium chloride, dried (Na₂SO₄), and concentrated to give thetitle compound (1.79 g, 87%) as a light pink solid. MS(ES+) m/e 541[M+H]⁺.

3-Chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate(1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) wasstirred at room temperature for 45 minutes. The reaction wasconcentrated to dryness and redissolved in DMF (30 mL). To this solutionwas added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) andpentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (1.36 g, 3.31mmol). The mixture was stirred overnight at room temperature, dilutedwith water, and extracted into ethyl acetate. The extracts were washedwith water, dried (Na₂SO₄), and concentrated in vacuo to give the titlecompound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]⁺.

N-[(1S)-2-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

A mixture of3-chloro-N-[(1s)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide(2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) inethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled,diluted with ethanol, filtered, and concentrated to give the titlecompound (1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]⁺.

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture ofN-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide(0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine(0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) inmethylene chloride (17 mL) was stirred overnight at room temperature.The reaction was diluted with water, washed with brine, dried (Na₂SO₄),and concentrated. The residue was purified by flash chromatography onsilica gel (8%-10% MeOH:CH₂Cl₂) to give the title compound (0.515 g,48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]⁺.

1,1-Dimethylethyl{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

A solution of 1,1-dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate(6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate(10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. Thereaction was then cooled to RT and a precipitate formed which wasfiltered, washed with cold hexanes (3×100 mL), and dried to afford thetitle compound as light gray solid (72%). ESMS [M+H]⁺: 576.2.

1,1-Dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)carbamate

Following the procedure described above with 3-methyl-2-pyridinamine,instead of 3-bromo-2-pyridinamine, provided the title product as a lightpink solid. ESMS [M+H]⁺:511.0.

N-{(1S)-2-[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide

A solution of1,1-dimethylethyl{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)methyl]ethyl}carbamate(3.5. mmol) and hydrogen chloride in 1,4-dioxane (20 mL, 4.0 M) wasstirred for 1 h at RT. The reaction was concentrated to dryness andredissolved in N,N-dimethylformamide (35 mL). Added to the solution wasdiisopropylethylamine (10.5 mmol) and pentafluorophenyl3-chloro-4-[(1-methylethyl)oxy]benzoate (3.8 mmol), followed by stirringat RT for half an hour. The reaction was dissolved in ethyl acetate (80mL) and washed with water (3×50 mL) and brine (1×50 mL). To theseparated organic layer was added hexanes (150 mL) upon which aprecipitate was formed, filtered, and dried to afford the title compoundas an off white solid (65%). ESMS [M+H]⁺: 672.2.

3-Chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

Following the procedure described above with1,1-dimethylethyl((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)carbamateprovided the title product as an off white solid. ESMS [M+H]⁺: 608.2.

N-((1S)-2-Amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

To a solution ofN-{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide(1.5 mmol) in ethanol (10 mL) was added hydrazine monohydrate (7.6mmol). The reaction stirred for 18 h at 50° C. upon which a whiteprecipitate formed and was filtered. The filtrate was concentrated invacuo. The resultant light yellow solid was used directly in the nextreaction without further purification. ESMS [M+H]⁺: 533.2

N-((1S)-2-Amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

Following the procedure described above with3-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamideprovided the title product as an off white solid. ESMS [M+H]⁺: 478.2.

N-((1S)-2-(D-Alanylamino)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

A solution ofN-((1S)-2-amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide(0.28 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol),EDCI (0.56 mmol), and TEA (1.12 mmol) stirred in methylene chloride (2mL) at RT for 18 h. The reaction was then treated with 4 M HCl in1,4-dioxane (2 mL) and stirred at RT for 1 h. The mixture was thenconcentrated in vacuo, redissolved in ethyl acetate (25 mL) and washedwith saturated aqueous sodium bicarbonate solution (1×10 mL). Theorganic layer was concentrated in vacuo, and purification of the residueby Gilson reverse phase HPLC afforded the title product as a white solid(25%). ESMS [M+H]⁺: 613.2.

3-Chloro-N-((1S)-2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

Following the procedure described above withN-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamideand N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine provided thetitle product as a white solid. ESMS [M+H]⁺: 563.2.

3-Chloro-N-((1S)-2-[(N,N-dimethylglycyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

Following the procedure described above withN-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamideand N,N-dimethylglycine provided the title product as a white solid.ESMS [M+H]⁺: 563.2.

2-Bromo-1-(4-iodophenyl)ethanone

A solution of 1-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL)was cooled to 10° C. Bromine (1.1 equiv, 61.6 mmol) was added dropwiseto the reaction mixture. After 10 min, the cooling bath was removed andthe reaction mixture was stirred at room temperature. After 1.5 h, thereaction mixture was concentrated in vacuo, poured into water (100 mL),and extracted with (3×100 mL) ethyl acetate. The combined organic layerswere dried over sodium sulfate and concentrated in vacuo to a tan solid(18.2 g) which was used directly in the next step.

2-(4-Iodophenyl)-8-methylimidazo[1,2-a]pyridine

A mixture of crude 2-bromo-1-(4-iodophenyl)ethanone (18.2 g),2-amino-3-picoline (1.1 equiv, 61.6 mmol), and sodium bicarbonate (1.3equiv, 72.8 mmol) in isopropanol (160 mL) was heated at 80° C. for 16 h.After concentrating the reaction mixture in vacuo, water (100 mL) wasadded and the resultant tan slurry was filtered, rinsing with water(2×50 mL). The brown solid was recrystallized from hot isopropanol andfurther dried in vacuo to provide the title product as a brown solid(13.2 g, 71%). ESMS [M+H]⁺: 335.0.

4-(4-Bromophenyl)-N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide

To a solution of ethyl4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylate (1.66 g, 5.37mmol) in MeOH (38 mL) was added 1N NaOH solution (19 mL). The reactionturned cloudy white and was stirred at room temperature for 30 minutes.The reaction mixture was concentrated in vacuo and pumped under highvacuum overnight to give the sodium salt of4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid as a whitesolid. The sodium salt of4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid was dissolvedin anhydrous CH₂Cl₂ (40 mL) under nitrogen at −15° C. (ice/methanolbath) and N-methylmorpholine (1.1 equiv, 5.91 mmol) was added followedby isobutyl chloroformate (1.1 equiv, 5.91 mmol). The reaction mixturewas stirred at −15° C. for 15 minutes and then N,O-dimethylhydroxylaminehydrochloride (1.0 equiv, 5.37 mmol) was added. The reaction was allowedto warm to room temperature and was stirred for 17 hours. The reactionwas quenched with H₂O (10 mL). The product was extracted using EtOAc(3×30 mL) and the combined organic layers were washed with brine (20mL), dried over MgSO₄, and concentrated in vacuo. Purification by silicagel chromatography (Analogix IF280, 20-100% EtOAc/hexanes) afforded thetitle compound as a tan solid (32%). ESMS [M+H]⁺: 324.2.

1,1-Dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate

Triethylamine (11.49 mL, 82.4 mmol) and ethyl chloroformate (8.27 mL,86.5 mmol) were added successively by syringe to N-t-Boc-D-glutamic acid5-tert-butyl ester (25 g, 82.4 mmol) in THF (588 mL) at <0° C. (ice-saltbath). After stirring in the cold bath for 40 min. solids were filteredand washed with THF (150 mL). The filtrate was transferred to a 250-mLaddition funnel and added to a solution of sodium borohydride (8.42 g,222.5 mmol) in H₂O (114 mL) at 0° C. over 1 hour. The reaction mixturewas maintained at 0° C. for 1.5 h and then stirred for 16 h (0° C. toroom temperature). After the bulk of solvents were removed by rotaryevaporation, the concentrate was quenched with ice water (50 mL) and 1 NHCl (50 mL). After extraction with EtOAc (4×100 mL), the extracts werewashed with 100 mL: 0.5 M citric acid, saturated NaHCO₃, H₂O, and brineand concentrated in vacuo to give the title compound, which was useddirectly in the next step. ESMS [M+H]⁺⁼290.4, [2M+H]⁺=579.4. (Literatureprep: J. Med. Chem, 1999, 42(1), 95-108 for other isomer).

1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate

To a solution of crude 1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate(23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) andimidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH₂Cl₂ under N₂ at 0°C. was added iodine over 15 min portionwise. The ice bath was removed,and the reaction was allowed to warm to room temperature and stirredover 30 min. The reaction was quenched with 200 mL H₂O, and the aqueouslayer was extracted with diethyl ether (2×150 mL). The combined organiclayers were washed with sat. aq. Na₂SO₃ solution (2×25 mL) and brine (25mL), dried over MgSO₄, and concentrated in vacuo. Purification of theresidue by silica gel chromatography (Analogix IF280, 5% -50% EtOAc/Hex)afforded the title compound as a white solid (25.34 g, 77%). ESMS[M+H]⁺=400.4.

1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoate

A flask containing zinc dust (6.0 equiv, 325 mesh, Strem) was heatedwith a heat gun while evacuating and filling with nitrogen (3 times).Under nitrogen, degassed DMF (14 mL) was added via syringe followed by1,2-dibromoethane (0.35 equiv). The grey reaction mixture was stirred inan oil bath at 100° C. for 15 minutes and then cooled to roomtemperature. Chlorotrimethylsilane (0.25 equiv) was added to the mixturevia syringe and the reaction was stirred at room temperature for 30minutes. A solution of 1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate (2.0g, 1.2 equiv) in degassed DMF (14 mL) was added to the reaction mixturevia cannula. The flask containing the solution was rinsed with degassedDMF (4 mL) and cannulated into the reaction mixture. The reaction wasstirred at room temperature for 1 hour. Then,tris(dibenzylideneacetone)dipalladium (0) (2.5 mol %),tri-o-tolylphosphine (10 mol %) and2-(4-iodophenyl)-8-methylimidazo[1,2-a]pyridine (1.4 g, 1.0 equiv) wereadded through the top all at once. The reaction mixture was stirred atroom temperature for 17 hours. The reaction was diluted with EtOAc (40mL) and filtered through Celite®. The filtrate was washed with H₂O (20mL) and brine (20 mL), and the organic layer was dried over MgSO₄ andconcentrated in vacuo. Purification by silica gel chromatography(Analogix IF280, 5-90% EtOAc/hexanes) afforded the title compound as awhite solid (90%). ESMS [M+H]⁺=480.4.

1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoate

Following the procedure described above using4-(4-bromophenyl)-N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamideprovided the title compound as a solid (82%). ESMS [M+H]⁺=517.2.

(4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoicacid

To a solution of1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoate(1.35 g, 2.82 mmol) in CH₂Cl₂ (14 mL) was added trifluoroacetic acid (10mL) followed by triethylsilane (2.5 equiv, 7.04 mmol). The reaction wasstirred for 45 minutes at room temperature and then concentrated invacuo. DMF (35 mL) was added to the residue followed by diisopropylamine(14.7 mL, 84.51 mmol) under nitrogen. The reaction was stirred for 5minutes and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate(1.1 equiv, 3.10 mmol) was added. The reaction was stirred for 45minutes and then concentrated in vacuo. Ethyl acetate (50 mL) was addedto the residue and it was washed with H₂O (30 mL). The aqueous layer wasextracted with EtOAc (20 mL) and the combined organic layers were driedover MgSO₄ and concentrated in vacuo. Purification by silica gelchromatography (Analogix IF280, 25-100% EtOAc/hexanes) provided thetitle compound as a white foamy solid (61%). ESMS [M+H]⁺=520.2.

(4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoicacid

Following the procedure described above with 1,1-dimethylethyl(4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoateand foregoing purification provided the title compound as a solid. ESMS[M+H]⁺=557.2.

(4R)-5-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]pentanoicacid

To a solution of crude(4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoicacid (3.18 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. wasadded methylmagnesium bromide (10.6 mL, 10 equiv, 3.0 M in ether)dropwise by syringe. The reaction was stirred for 30 minutes at 0° C.and then carefully quenched with sat. aq. NH₄Cl solution (10 mL),followed by 1 N HCl solution (60 mL) such that the pH of the aqueouslayer ˜5.5. The product was extracted with EtOAc (4×40 mL) and thecombined organic layers were dried over MgSO4 and concentrated in vacuoto give the title compound, which was used directly in the nextreaction. ESMS [M+H]⁺=512.4.

N-((1R)-4-Amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-4-oxobutyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

To a solution of(4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoicacid (900 mg, 1.73 mmol) in anhydrous THF (12.4 mL) at 0° C. undernitrogen was added triethylamine (242 uL, 1.73 mmol) followed by ethylchloroformate (174 uL, 1.82 mmol). The reaction was stirred for 40 minat 0° C. and then the solids were filtered and washed with 5 mL THF. Thefiltrate was added to a flask containing NH₄OH (5 mL) at roomtemperature and the reaction mixture was stirred for 1 hour. The productwas extracted from the reaction mixture with EtOAc (50 mL). The aqueouslayer was extracted with EtOAc (20 mL) and then acidified with 1N HClsolution (30 mL) and re-extracted with EtOAc (10 mL). The combinedorganic layers were dried over MgSO₄ and concentrated in vacuo to give awhite solid. Purification by recrystallization from hot isopropanolafforded the title compound as a white solid (90%). ESMS [M+H]⁺=519.4.

N-((1R)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

Following the procedure described in above with(4R)-5-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]pentanoicacid and purification by Gilsin reverse phase HPLC provided the titlecompound as a white solid. ESMS [M+H]⁺=511.2.

(3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyldimethyl phosphate

To a solution ofN-((1s)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide(500 mg, 1.04 mmol) in dry CH₂Cl₂ (10 mL) under N₂, was added dimethylchlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol)at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed ˜50% conversion, so anadditional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) andDMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, thereaction was quenched with saturated aqueous NH₄Cl and diluted withCH₂Cl₂. The aqueous layer was back-extracted with CH₂Cl₂ and thecombined organics were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the titlecompound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M+H)⁺. Note thatthe product was contaminated with ˜1 eq of the starting dimethylchlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is.

(3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyldihydrogen phosphate

A yellow solution of(3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyldimethyl phosphate (475 mg, 0.804 mmol) in 30% HBr in AcOH was placed ina pre-heated (60° C.) bath for 10 min, then immediately allowed to coolto rt. The reaction mixture was concentrated under reduced pressure andthe residue was dissolved in DMSO (6 mL), filtered and purified byGilson reverse phase HPLC (MeCN/H₂O with 0.1 % TFA). The MeCN of theclean fractions was removed under reduced pressure and the remainingaqueous solution was frozen and lyophilyzed overnight to give 84 mg(19%) of the title compound as a yellow powder. LC/MS (ES) m/e 564.2(M+H)⁺.

(3S)-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]butyldihydrogen phosphate

Following the procedures described above, except substituting3-chloro-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamideforN-((1S)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamideand potassium tert-butoxide for DMAP, the title compound was prepared asa white powder (35% yield). LC/MS (ES) m/e 563 (M+H)⁺.

3-Cyano-N-[(1S)-1-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

To a solution ofN-((1S)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide(200 mg, 0.366 mmol) in dry DMF (2 mL) were added3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol),tetrakistriphenylphosphine palladium(0) (21 mg, 0.018 mmol) and 2.0 Maqueous K₂CO₃ (0.46 mL) successively at rt. The reaction mixture waspurged with argon and heated to 100° C., stirred for 22 h, cooled to rt,filtered and purified directly by reverse phase HPLC (MeCN/H₂O with 0.1%TFA). The clean fractions were adjusted to pH ˜8 with saturated aqueousNaHCO₃ and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure to give45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m/e564.2 (M+H)⁺.

3-chloro-N-((1S)-1-{[3-chloro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

Following the procedures described in the literature (J. Org. Chem.2003, 68, 4215; J. Org. Chem. 2002, 67, 1738; J. Am. Chem. Soc. 1972,94, 6203), as well as the procedures above, the title compound wasprepared as a white solid. LC/MS (ES) m/e 526 (M+H)⁺.

The following compounds were prepared using the procedures describedabove:

Structure Name (M+H)⁺

N-((1R)-1-{[4-(2-Acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-[(1R)-4-Amino-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-4-oxobutyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(hydroxyacetyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}-1-{[(N,N-dimethylglycyl)amino]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({[(2R)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-[(Aminocarbonyl)amino]-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-{(1S)-2-[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(2-oxotetrahydro-1(2H)-pyrimidinyl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-{(1S)-2-[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(2-oxohexahydro-1H-1,3-diazepin-1-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-[(Aminocarbonothioyl)amino]-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-3-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]propyl}phenyl)imidazo[1,2-a]pyridine-8-carboxamide

N-((1S)-2-[(Aminosulfonyl)amino]1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

(3S)-3-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}butanoicacid

N-[(1S)-2-[(Aminosulfonyl)amino]-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(1H-Benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[5-(methyloxy)-1H-benzimidazol-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(5-chloro-1H-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-3-hydroxy-1-{[4-(4-methyl-1H-benzimidazol-2-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

Ethyl2-(4-{(2S)-2-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-1H-benzimidazole-5-carboxylate

2-(4-{(2S)-2-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-1H-benzimidazole-5-carboxylicacid

N-((1S)-3-Amino-1-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}propyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-1-{[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(8-Chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-hydroxyimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxamide

Ethyl2-(4-{(2S)-2-[({3-cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxylate

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-nitroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(8-Aminoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-8-carboxamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-1-({4-[8-(Aminomethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-(2-hydroxyethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-1-({4-[1-[2-(Acetylamino)ethyl]-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1R)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]-propyl}-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

N-[(1R)-4-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-4-oxobutyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

N-[(1R)-4-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-4-oxobutyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(3-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-1-{[4-(3-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-4-[(1-methylethyl)oxy]-N-[(1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-(4-morpholinylmethyl)ethyl]benzamide

3-Chloro-N-((1S)-2-(4-hydroxy-1-piperidinyl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-(3-hydroxy-1-pyrrolidinyl)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-4-[(1-methylethyl)oxy]-N-((1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-{[(2,2,2-trifluoroethyl)amino]methyl}ethyl)benzamide

3-Chloro-N-((1S)-2-[(2-hydroxyethyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-1-{[4-(8-ethyl-5-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

Methyl(3S)-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[(phenylcarbonyl)amino]phenyl}butanoate

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[(phenylcarbonyl)amino]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-{(1S)-1-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)methyl]-3-hydroxypropyl}-4-[(1-methylethyl)oxy]benzamide

Phenylmethyl(4-{(2S)-2-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)carbamate

3-Chloro-N-((1S)-3-hydroxy-1-{[4-({[2-(methylamino)phenyl]carbonyl}amino)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

N-(4-{(2S)-2-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)-4-pyridinecarboxamide

3-Chloro-N-[(1S)-1-({4-[(cyclohexylcarbonyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({4-[(3,3-dimethylbutanoyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-3-hydroxy-1-({4-[(phenylacetyl)amino]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-{(1S)-3-hydroxy-1-[(4-{[(phenylamino)carbonyl]amino}phenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(1-methyl-3-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-6-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

2,3-Dichloro-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

N-((1S)-3-Hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}methyl}propyl)-4-[1-methylethyl)oxy]-3-nitrobenzamide

3-Chloro-N-[(1S)-2-[(hydroxyacetyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({](2R)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1s)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-({[(2S)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-2-(D-Alanylamino)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1-{[(2-methylalanyl)amino]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

(3S)-3-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[(phenylcarbonyl)amino]phenyl}butanoicacid

3-Chloro-N-{(1s)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-6-ylphenyl)methyl]propyl}-4[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)imidazo[1,2-a]pyridin-6-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-2-ylphenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyrimidin-2-ylphenyl)methyl]propyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-3-hydroxy-1-{[4-(5-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-3-hydroxy-1-{[4-(7-methylimidazo[1,2-a]pyrimidin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-{(1S)-3-hydroxy-1-[(4-imidazo[2,1-b][1,3]thiazol-6-ylphenyl)methyl]butyl}-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}butyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-1-{[4-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}-3-hydroxybutyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-1-{[4-(1,1-dioxido-2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]methyl}-3-hydroxybutyl)-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-1-({4-[1-(3-Aminopropyl)-2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-4-[(1-methylethyl)oxy]-N-[(1S)-2-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]benzamide

3-Cyano-N-[(1S)-1-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}propyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(4-isoxazolyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide

Ethyl(2E)-3-[2-(4-{(2S)-2-[({3-cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridin-8-yl]-2-propenoate

(2E)-3-[2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}phenyl)imidazo[1,2-a]pyridin-8-yl]-2-propenoicacid

N-{(1S)-1-[(4-{8-[(1E)-3-Amino-3-oxo-1-propen-1-yl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-1-({4-[8-(3-Amino-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[4-(3-chloro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

N-((1S)-1-{[4-(3-Chloro-8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-1-({3-fluoro-4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-hydroxy-1-{[5-(8-methylimidazo[1,2-a]pyridin-2-yl)-2-pyridinyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-hydroxy-1-{[5-(8-methylimidazo[1,2-a]pyridin-2-yl)-2-thienyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2-fluorophenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2,6-difluorophenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({2-chloro-4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({5-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]-2-pyridinyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[2-chloro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[2-chloro-4-(8-chloroimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-1-{[2,5-difluoro-4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-3-(methylamino)-3-oxopropyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-({[(phenylamino)carbonyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-({[(ethylamino)carbonyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

N-[(1S)-2-(Aminosulfonyl)-1-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-((1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-{[(methylsulfonyl)amino]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-{(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1[({[(2-hydroxyethyl)amino]carbonyl}amino)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

N-[(S)-1-[4-(2-tert-Butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-(2-methoxy-ethanoylamino)-ethyl]-3-cyano-4-isopropoxy-benzamide

(4R)-4-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}pentanoicacid

3-Cyano-N-{(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}-1-[(2-oxo-1-imidazolidinyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-Amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

N-((1S)-2-(Acetylamino)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-((1S)-2-{[(2R)-2-hydroxypropanoyl]amino}-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Cyano-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[2-(1-hydroxy-1-methylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

To a 0° C. solution of compound 1 (10.7 g, 61.37 mmol) and(R)-1,1,1-trifluoropropanol (3.5 g, 30.68 mmol) in dimethylformamide(200 mL) was added sodium hydride (3.7 g, 92.05 mmol) portionwise over 5minutes. After 10 min, the ice bath was removed and the reaction mixturewas stirred while warming to room temperature. The reaction mixture washeated to 80° C. and stirred overnight. The reaction was monitored byLC/MS until complete. After cooling to room temperature, the reactionmixture was quenched with HCl (0.5N, 200 mL) and extracted with ethylacetate (3×250 mL). The organic layer was dried over sodium sulfate,filtered, and the filtrate was concentrated in vacuo giving crudecompound 2 (8.2 g) which was used directly in the next step withoutfurther purification.

To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol) andtriethylamine (6.4 mL, 46.02 mmol) in dicholoromethane (200 mL) wasadded pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) viasyringe over 3 min. After another 5 min, the ice bath was removed andthe reaction mixture stirred while warming to room temperature foranother 2 hours. The reaction mixture was concentrated in vacuo, and theresulting residue purified by flash chromatography (silica gel,hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).

Methyl 4-hydroxy-3-iodobenzoate 2: Methyl 4-hydroxybenzoate (35.5 g,0.233 mol) was dissolved in 200 mL of acetic acid, and the stirredmixture was warmed to 65° C. A solution of ICl (37.8 g, 0.233 mol) in 50mL of AcOH was added dropwise over 40 min. The mixture was stirred at65° C. for 5 h and then stirred an additional 16 h at room temperature.The precipitated product was isolated via filtration, washed with waterand dried under vacuum to give 27.5 g (99% pure by LCMS and HNMR)) ofdesired product. The mother liquors were evaporated and the resultingresidue was washed with water and dried under vacuum to give another 31g (95% pure by LCMS and NMR) of desired product. The combined yield ofmethyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3% yield).

Methyl 3-cyano-4-hydroxybenzoate 3: 28 g (0.1 mol) of methyl4-hydroxy-3-iodobenzoate 2 dissolved in 100 mL of DMF was treated with9.92 g (0.11 mol) of CuCN and 0.49 g (0.11 mol) of NaCN. The system wasflushed with nitrogen after which the mixture warmed to 105° C. andstirred to 18 h. The mixture was allowed to cool to room temperature,and any precipitates were removed via filtration and washed with EtOAc.The combined organics were diluted with 200 mL of water and thenextracted with EtOAc (2×200 mL). The combined layers were dried oversodium sulfate, filtered and evaporated to dryness. After drying undervacuum, the resulting 18 g (100% yield) of 3 was characterized by LCMSand HNMR.

Methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate3 (18 g, 0.1 mol) was dissolved in 100 mL of DMF and treated with 14.2mL (0.15 mol) of 2-bromopropane and 41.9 g (0.3 mol) of anhydrouspotassium carbonate. The system was flushed with nitrogen, and themixture was heated to 90° C. with stirring overnight. After cooling toroom temperature, the mixture was diluted with 200 mL of water andextracted with CH₂Cl₂ (2×200 mL). The combined organic layers were driedover sodium sulfate, filtered and evaporated to dryness to give 20.5 g(99% yield) of 4 as an oil that was characterized by LCMS and HNMR.

Perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: 20.5 g (0.093 mol) ofmethyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6:4mixture of methanol and water. To this was added 5.61 g (0.14 mol) ofNaOH and the mixture stirred for 2 hours at room temperature. Thesolution was then filtered through a silica gel plug and the solventsremoved under vacuum. The resulting solid was re-dissolved in 200 mL ofCH₂Cl₂ and treated with 19.3 mL (0.11 mol) of perfluorophenyl2,2,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. Afterstirring overnight, the solution was filtered and any solids rinsed withCH₂Cl₂. The combined organic fractions were run through a short silicagel column and then evaporated to dryness to give 29 g (83.5% yield) of6 which was characterized by LCMS and HNMR.

To a solution of compound 1 (200 mg, 1.077 mmol) and 2-iodopropane (322uL, 3.23 mmol) in DMF (10 mL) was added DIEA (750 uL, 4.31 mmol). Thereaction mixture was heated to 80° C. and stirred overnight. Whencomplete by LC/MS, the reaction was cooled to room temperature, quenchedwith HCl (0.5 N, 30 mL) and extracted with ethyl acetate (50 mL×3). Thecombined organic layers were dried over sodium sulfate, concentrated anddried under high vacuum. The resulting residue was purified by reversephase chromatography using a mixture of acetonitrile and water to givecompound 2 (50 mg, 20%).

To a solution of compound 2 (50 mg, 0.22 mmol) in MeOH (1.0 mL) wasadded aqueous NaOH (1.0 M, 330 uL, 0.330 mmol). The reaction mixture wasstirred at ambient temperature for 2 hours and monitored by LC/MS. Thereaction mixture was quenched with HCl (0.5 N, 5 mL) and extracted withethyl acetate (10 mL×3). The organic layer was dried over sodium sulfateand concentrated to give 3 (45 mg). LRMS (M−H⁺) m/z 212.0

To a suspension of 4-azidobenzoic acid (5.00 g, 30.7 mmol) indichloromethane (95 mL) was added diisopropylethylamine (10.7 mL, 61.4mmol), which immediately turned the mixture into a clear solution.Pentfluorophenyltrifluoroacetate (9.44 g, 33.7 mmol) was added and themixture stirred at room temperature for 1 h, at which time TLC showedclean desired product. The mixture was washed with water (2×100 mL),dried over Na2SO4, and concentrated under vacuum to provide the desiredproduct (9.02 g) as a viscous oil which was carried on to the next step.

A stirred mixture of the above oil 2 (∞27 mmol) in THF (100 mL) wastreated with triphenylphosphine (7.20 g, 27.4 mmol) portionwise to avoidfrothing. The mixture was stirred an additional 20 min, after whichLC/MS showed complete conversion of starting material. The solvents wereremoved under vacuum and the resulting residue used in the next stepwithout purification. LRMS (M+H⁺) m/z 564.1.

A portion of residue 3 (4.19 g, ˜7.45 mmol) was dissolved inacetonitrile (50 mL) and treated with N-chlorosuccinimide (1.19 g, 8.94mmol) at room temperature. The temperature was raised to 65° C. and themixture stirred overnight. When LC/MS showed complete conversion ofstarting material, the mixture was cooled to room temperature andpartitioned between water (150 mL) and ethyl acetate (150 mL). Theorganic layer was separated and the organic phase washed twice with 2 NNa₂CO₃ and brine, dried over Na₂SO₄ and concentrated under vacuum togive an off white solid. The product was purified by preparative reversephase HPLC to give pure desired product 4 (1.31 g, 29% from s.m.) as awhite foamy solid upon solvent evaporation and high vacuum drying. LRMS(M+H⁺) m/z 598.0.

To a stirred solution of 4 (1.31 g, 2.19 mmol) in benzene (20 mL) wasadded 1,1,1-trifluoroacetone (3.92 mL, 43.7 mmol) and the mixturestirred at 65° C. overnight. When LC/MS confirmed that most of thestarting material was consumed, the solvent was evaporated and the crudeproduct purified by preparative HPLC over silica using ether and hexanesas eluent to give desired product 5 (369 mg, 39%) as a white solid. LRMS(M−H⁺) m/z 430.0.

To a mixture of amine 6 (129 mg, 0.408 mmol) in DMF (3 mL) were addeddiisopropylethylamine (284 uL, 1.63 mmol) and active ester 5 (211 mg,0.49 mmol) at room temperature. The reaction was stirred 30 min andevaporated to dryness under vacuum. Half the residue was purified bypreparative HPLC over silica using ethyl acetate and hexanes as eluentto give pure 7 (65 mg, 56%). LRMS (M+H⁺) m/z 565.2.

Imine 7 (60 mg, 0.106 mmol) was dissolved in methanol (3 mL) and treatedwith sodium borohydride (100 mg, 0.3 mmol). The mixture was stirred atroom temperature for 30 min, at which time LC/MS showed clean desiredproduct. The solvent was evaporated under vacuum and the residuere-suspended in ethyl acetate. The solution was washed twice with 0.1 MKOH, dried over Na₂SO₄, and concentrated to a crude glassy solid whichwas purified by preparative HPLC over silica using ethyl acetate andhexanes as eluent. The product still contained impurities and waspurified again under the same conditions to give clean 8 (49 mg, 82%) asthe racemate. LRMS (M+H⁺) m/z 567.1.

4-bromo-2-chlorophenol (5.04 g, 24.3 mmol) was dissolved in DMF (30 mL)and to it was added K₂CO₃ (10.10 g, 72.9 mmol) followed by2-chloroethyl-p-toluenesulfonate (4.86 mL, 26.7 mmol). The resultingmixture was heated to 60° C. for 3 hours and then cooled to roomtemperature. The reaction was diluted with EtOAc (350 mL) and washedwith water (5×150 mL). The organic phase was dried (Na₂SO₄) andconcentrated to a viscous oil which solidified to a white solid whileunder high vacuum. Compound 2 (6.46 g, 24.1 mmol, quantitative yield)was characterized using ¹H NMR and used in the following step withoutfurther purification.

A solution of compound 2 (6.46 g, 24.1 mmol) in DMF (30 mL) was treatedwith sodium hydride (1.94 g of 60% dispersion in mineral oil, 48.6 mmol)portionwise at room temperature. The resulting mixture was stirred atroom temperature for 16 hours and then partitioned between water (100mL) and EtOAc (350 mL). The layers were separated, and the organic layerwas washed with water (4×150 mL). The organic phase was dried (Na₂SO₄)and concentrated to a white solid. Compound 3 (5.56 g, 24.0 mmol,quantitative yield) was dried under high vacuum and characterized using¹H NMR. It was used in the following step without further purification.

Compound 3 (5.56 g, 24.0 mmol) was added to a solution ofchloroiodomethane. (5.59 mL, 76.8 mmol) in 1,2-dichloroethane (35 mL)under an atmosphere of nitrogen. The solution was cooled to 0° C. withan ice bath and diethyl zinc (38.4 mL, 1.0 M in hexanes, 38.4 mmol) wasadded over 10 minutes. The resulting mixture was stirred for 30 minutesand allowed to warm to room temperature. It was again cooled to 0° C.with an ice bath, and saturated aqueous NH₄Cl (150 mL) was added,followed by concentrated aqueous NH₄OH (25 mL) and EtOAc (200 mL). Thelayers were separated and the aqueous phase was extracted withadditional EtOAc (2×100 mL). The organic phases were combined, dried(Na₂SO₄) and concentrated to a crude oil which was purified over silicagel (100% hexanes) to yield compound 4 (1.76 g, 7.2 mmol, 30% yield) asa colorless oil which was characterized using ¹H NMR.

In a high-pressure reactor, compound 4 (1.76 g, 7.2 mmol) was dissolvedin EtOH (40 mL). Triethylamine (5.0 mL 35.8 mmol) was added, followed by[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (188 mg,0.36 mmol). The reaction vessel was pressurized with carbon monoxide(100 psi), evacuated and repressurized with carbon monoxide (100 psi).The vessel was evacuated and pressurized once more with carbon monoxide(350 psi) and then heated to 90° C. with stirring for 16 h. The mixturewas cooled to room temperature, depressurized and filtered throughcelite. The solvents were evaporated, and the remaining residue waspartitioned between dichloromethane (150 mL) and 1 M aqueous KHSO₄ (75mL). The layers were separated and the organic phase was washed withadditional 1 M aqueous KHSO₄ (1×75 mL). The organic phase was dried(Na₂SO₄) and concentrated to an oil which was purified using silica gel(EtOAc/Hexanes), providing compound 5 (648 mg, 2.70 mmol, 38% yield) asa white solid. The product was characterized using ¹H NMR.

To a solution of compound 5 (648 mg, 2.70 mmol) in dichloromethane (3mL) and EtOH (15 mL) was added 1 M aqueous KOH (7 mL, 7 mmol). Theresulting cloudy mixture was heated to 60° C. for 1 h. Thedichloromethane and EtOH were evaporated under reduced pressure, and theremaining aqueous solution was acidified using concentrated HCl. Theresulting precipitate was filtered to give compound 6 (506 mg, 2.39mmol, 88% yield) as a pure white solid that was characterized usingLC/MS (LRMS (M-H) 211.1 m/z).

To a solution of amine 1 (580 mg, 1.7 mmol) and triethylamine (449 μL,3.4 mmol, 2 eq.) in THF (8.5 mL, 0.2 M), was added chloroethylchloroformate (278 μL, 2.6 mmol, 1.5 eq). The mixture was stirred for 30min at room temperature, and then diluted in ethyl acetate and washedwith 1 N HCl and brine. The organic layer was dried, filtered, andconcentrated in vacuo to yield a yellow oil (900 mg). To a solution ofthe crude material in DMF (10 mL) was added NaH (272 mg, 6.8 mmol, 4 eq)and the mixture stirred at room temperature for 16 h. The solution wasdiluted with ethyl acetate (100 mL) and washed with brine (5×50 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo to yield crudethe product as an oil. Purification by flash silica gel chromatography(1:1 ethyl acetate:hexanes) gave 800 mg (24%) of the desired product.m/z (+1)=398.0.

To a 100 mL round bottom flask was added (R)-benzyl1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethylcarbamate (1.50 g,3.27 mmol, 1.0 equiv), CH₃CN (20 mL), and TMSI (900 μL, 6.3 mmol, 1.9equiv). The reaction mixture was capped and stirred for 2 hours.Methanol (40 mL) was then added to the flask and the mixture wasconcentrated, dissolved in EtOAc (100 mL), and washed with water. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was dissolved in dichloromethane and purified by silica gelchromatography (35-60% CH₃CN/CH₂Cl₂, then 20% MeOH/CH₂Cl₂) to afford 950mg (90%) of the desired primary amine as an oil (M+H (m/z)=328). To thisamine was added CH₂Cl₂ (20 mL) and pyridine (260 μL, 1.1 equiv),followed by 4-chlorobutyryl chloride (344 μL, 1.05 equiv) in a dropwisefashion. The reaction was stirred for 15 min, followed by the additionof EtOAc (50 mL) and water (10 mL). The organic layer was separated,dried over Na₂SO₄, filtered, and concentrated. The residue was dissolvedin dichloromethane and purified by silica gel chromatography (5-35%CH₃CN/CH₂Cl₂) to afford 747 mg (60%) of(R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)butanamideas an off-white solid (M+H (m/z)=432).

To a 20-dram vial was added(R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)butanamideand THF (10 mL). The vial was cooled to 0° C. under a nitrogenatmosphere and potassium t-butoxide (214 mg, 1.91 mmol) was added. Thereaction was stirred for 1.5 h. To the reaction mixture was added EtOAc(50 mL) and water (10 mL). The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated. The residue was then dissolved indichloromethane and purified by silica gel chromatography (5-50%CH₃CN/CH₂Cl₂) to afford 593 mg (86%) of(R)-1-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)pyrrolidin-2-oneas a white solid (M+H (m/z)=396).

To a solution of 1 (10 g, 45.7 mmol) in DMF (150 mL) were added HBTU (26g, 68.5 mmol), dimethylhydroxylamine HCl salt (5.35 g, 54.8 mmol) andDIEA (9.6 mL, 55.0 mmol) at 0° C. After stirring 2 h, the mixture wasallowed to warm to room temperature and stirring continued for 2 days.The reaction mixture was partitioned between EtOAc (500 mL) and H₂O (200mL), and the organic layer washed with NaOH (2 N, 200 mL), HCl (2 N, 200mL), H₂O, and brine, dried over Na₂SO₄, and concentrated to give 2 (9.6g), which was used without further purification. LRMS (M+H⁺) m/z 262.0.

To a solution of 2 (9.6 g, ˜36.8 mmol) in Et₂O (100 mL) was added MeMgBr(3 M in Et₂O, 27 mL) at 0° C. The resulting mixture was allowed to warmto room temperature and then stirred 4 h. The reaction mixture wasquenched with saturated NH₄Cl (100 mL), and the organic layer was washedwith H₂O and brine, dried over Na₂SO₄, and concentrated to give 3 (7 g,71% from 1), which was characterized by NMR.

To a solution of 3 (6.5 g, 30 mmol) in dichloromethane (200 mL) and MeOH(100 mL) was added tetrabutylammonium tribromide (14.5 g, 30 mmol) andthe mixture stirred for 14 h. The solvents were removed under vacuum andthe product dried under high vacuum to give 4 (characterized by NMR),which was used in the next step without further purification.

To a solution of 4 (5 g, ˜16.9 mmol) in dichloromethane (50 mL) wasadded hexamethylenetetramine (2.6 g, 18.5 mmol), and the reactionmixture was stirred for 2 h. The mixture was diluted withdichloromethane (500 mL) and the precipitate collected, washed withdichloromethane (500 mL×2), and dried under high vacuum. To theresulting residue was added EtOH (60 mL) and concentrated HCl (30 mL).The reaction mixture was stirred for 2 h, after which the mixture wasconcentrated and dried under high vacuum to give 5, which was usedwithout further purification. LRMS (M+H⁺) m/z 231.9.

To a solution of crude 5 (˜16.9 mmol) in dioxane (50 mL) were addedNaOAc (6.93 g, 84.5 mmol), HOAc (4.8 mL, 84.5 mmol), and 5.1 (5.93 g,84.5 mmol). After 1 h, the reaction mixture was warmed to 80° C. andstirred for 3 h. The reaction mixture was partitioned between EtOAc (500mL) and saturated NaHCO₃ (200 mL). The aqueous layer was extracted withEtOAc (300 mL×2), and the combined organic layers washed with brine,dried over Na₂SO₄, and concentrated. The resulting residue was purifiedon silica gel (Hex/EtOAc, 1:0, 1:2, 1:1, 0:1) to give 6 (1.2 g, 23% from4). LRMS (M+H⁺) m/z 312.9.

To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane(400 mL) was slowly added trimethyloxonium tetrafluoroborate (13.1 g, 89mmol) at 0° C. After 10 min the ice bath was removed, and the reactionmixture was stirred overnight. The solvent was removed to give 18.0 g ofproduct 2 as a white solid, which was used without further purification.

A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol),sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) andcompound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C.until TLC showed no compound 2 left (about 2 h). The reaction mixturewas carefully neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate. The organic solution was dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography (EtOAc:Hex1:1) gave product 4 (9.11 g, 79%) as a white solid.

In a round-bottom flask, product 4 (2.00 g, 6.8 mmol) was dissolved inDMF (20 mL), followed by the addition of iodomethane (5.1 mL, 10.1mmol), and K₂CO₃ (1.4 g, 10.1 mmol). The mixture was allowed to stir at60° C. for 3 hours until complete by TLC. The solution was quenched withbrine, extracted three times with EtOAc, dried over sodium sulfate andconcentrated. Purification via column chromatography using EtAc:Hex 1:1gave 1.381 g (66% yield) of product 5.

To a solution of compound 4 (5.307 g, 18 mmol) in DMF (15 mL) was addedK₂CO₃ (3.73 g, 27 mmol) and iodoethane (3.5 mL, 43.2 mmol). Theresulting mixture was stirred at 60° C. for three hours. The mixture wasdiluted with water and extracted with EtOAc (3×50 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. Purificationwith column chromatography (Hex/EtOAc 50:50) gave product 6 (3.2 g, 55%)

To a solution of compound 4 (3.174 g, 10.8 mmol) in DMF (15 mL) wasadded K₂CO₃ (4.478 g, 32.4 mmol) and(2-bromoethoxy)-tert-butyldimethylsilane (2.780 mL, 13.0 mmol). Theresulting mixture was stirred at 55° C. overnight. The solution wasconcentrated, diluted with water and extracted with EtOAc (3×50 mL). Theorganic layers were combined and dried over Na₂SO₄. The solvent wasremoved to give 7 as a viscous oil (4.805 g, 10.6 mmol, 98.4%), whichwas used in the subsequent step without further purification.

To a solution of compound 7 (2.174 g, 4.8 mmol) in anhydrous THF (25 mL)was added dropwise methylmagnesium bromide (4.8 mL, 3 M in diethylether, 14.4 mmol) under nitrogen at 0° C. The reaction was stirred at 0°C. for 15 minutes. The reaction was carefully quenched with saturatedammonium chloride solution (5 mL) and water (30 mL) and extracted withEtOAc (3×50 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated to a crude oil. Purification by flash column chromatography(15% EtOAc/Hex) gave the desired product 8 (1.371 g, 65%) as a whiteamorphous solid.

To a solution of compound 8 (1.371 g, 3.1 mmol) in THF (5 mL) was added35 mL of HCl (4 M in 1,4-dioxane). The resulting solution was stirred atroom temperature overnight. The solvents were removed to give product 9(1.0 g, 99%) as a white solid.

A mixture of compound 8 (0.5 g, 1.54 mmol) and 1 mL of TFA in toluene(60 mL) was refluxed overnight. The solid 8 did not dissolve untilaround the boiling point of toluene. The solvent was removed undervacuum. The residue was diluted with EtOAc, washed with NaHCO₃ aqueoussolution, dried over Na₂SO₄, and concentrated. Purification by flashcolumn chromatography (EtOAc:Hex 1:1) gave product 9 (0.348 g, 74%) as awhite solid.

Example 77

To a 250 mL round bottom flask was added(R)-1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)-N-methylethanamine(3.1 g, 9.1 mmol), methyl chloroformate (0.84 mL, 10.9 mmol), Na₂CO₃(1.15 g, 10.9 mmol), and THF (100 mL). The reaction was stirred for 2hours, followed by the addition of EtOAc (50 mL) and water (10 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to give1.50 g (41%) of (R)-methyl1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl(methyl)carbamate asan off-white solid (M+H (m/z)=400).

Example 78

Ref: J. Med. Chem. 2001, 44, 2990-3000

To a stirring solution of p-iodoacetophenone 1 (30.0 g, 122 mmol) indioxane (200 mL) over an ice-bath was added bromine (6.56 mL, 128 mmol)dropwise. The reaction mixture was stirred at room temperature andmonitored by LC/MS. After completion (about 1 hour), the solvent wasevaporated by rotovap, and the residue was dried under vacuum to givesolid 2 (40 g, 100%).

(Based on J. Med. Chem. 2001, 44, 2990-3000) To a solution ofCbz-D-Ala-OH (5.0 g, 22.4 mmol) in NMP (100 mL) was added cesiumcarbonate (3.72 g, 11.4 mmol). After stirring at RT for 1 h, 2 (7.60 g,22.4 mmol) was added. The reaction mixture was stirred at roomtemperature and monitored by LC/MS. The reaction solution was dilutedwith xylene (100 mL) and ammonium acetate (9.25 g, 120 mmol) and thenstirred at 120° C. for 4 hours. Up to 50 eq of additional ammoniumacetate may be needed depending on the reaction progress. The key is tosee solid in the flask at all times. After cooling to room temperature,the reaction mixture was diluted with ethyl acetate (200 mL). The EtOAcsolution was washed with saturated sodium bicarbonate solution (200 mL)twice, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was dissolved in dichloromethane (100 mL)and stirred for 1 h to give a precipitate. Solid 5 (4.0 g) was filteredoff and dried under vacuum. The mother solution was concentrated byrotovap and the residue purified by preparative HPLC over silica gel togive additional 5 (Hex:EtOAc 1:1 to EtOAc 100%). The two products werecombined and dried under vacuum to give a total of 5.8 g of 5 (58%).

Example 79

A stirred mixture of (R)-benzyl1-(4-(4-iodophenyl)-1H-imidazol-2-yl)ethylcarbamate 1 (5 g, 11 mmol) in55 mL of DMF was cooled to 0° C. and treated with NaH (1.33 g, 60%dispersion in oil, 33 mmol) in small portions to avoid foaming. Whenbubbling from the last portion ceased, MeI (2.1 mL, 34 mmol) was addedall at once and the mixture stirred an additional 30 min. The solventswere removed under vacuum and the residue dissolved in 200 mL of EtOAc.The solution was washed with saturated NH₄Cl (4×100 mL) and saturatedNaCl (4×100 mL), and then filtered and evaporated to dryness. The cruderesidue was purified via flash column chromatography over silica gel(60:40, EtOAc/Hex) to give 5.13 g (97% yield) of 2 which wascharacterized by LCMS.

To a solution of compound 3 (2.66 g, 7.27 mmol) in DMF (15 mL) was addedK₂CO₃ (2.00 g, 15 mmol) and ethyl bromoacetate (1.61 mL, 14.5 mmol). Theresulting mixture was stirred at 60° C. for three hours. The mixture wasdiluted with water and extracted with EtOAc (3×50 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. Purificationwith column chromatography (hexanes/EtOAc 50:50) gave the product 4(3.02 g, 91%).

To a solution of compound 4 (3.02 g, 6.7 mmol) in MeOH (20 mL) was addedHCl (4.0 M) in Dioxane (7.0 mL) and stirred at 60° C. for one hours. Themixture was concentrated and no purification was done. The resulting oilwas dissolved in DMF (15 mL), added K₂CO₃ (2.0 g, 14.7 mmol) was added,and stirred at 60° C. for overnight. The mixture was diluted with waterand extracted with EtOAc (3×50 mL). The organic layers were combined,dried over Na₂SO₄, and concentrated. Purification with columnchromatography (hexanes/EtOAc 50:50) gave the product 5 (1.80 g, 88%).

To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was addedK₂CO₃ (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4.56 g, 20.35mmol). The resulting mixture was stirred at 60° C. for three hours. Themixture was diluted with water and extracted with EtOAc (3×50 mL). Theorganic layers were combined, dried over Na₂SO₄, and concentrated.Purification with column chromatography (Hexanes/EtOAc 50:50) gave theproduct 4 (4.08 g, 55%) as white solid.

Example 80

Acetyl chloride (54.6 mL, 0.75 mol) was added drop-wise into ethanol(316 mL) at 0-5° C. When the addition was completed, the ice bath wasremoved and the solution allowed to stir while warming to roomtemperature for another 30 min. D-aspartic acid 1 (25 g, 0.188 mol) wasthen added. The reaction mixture was refluxed for 2 hours. The reactionsolution was then concentrated in vacuo and placed under high vacuum(0.4 mm Hg) overnight. Compound 2 was obtained as a white solid (42 g,99%) and used directly in the next step.

(Boc)₂O (44.7 g, 0.21 mol) was added portion-wise over 10 min to a 0° C.solution of compound 2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37mol), dioxane (140 mL) and water (56 mL). After another 10 min, the icebath was removed and the reaction mixture was stirred while warming toroom temperature for another 2 hours. The reaction mixture was dilutedin ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL×3). Theorganic layer was dried over magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo giving compound 3 (52 g, yield 97%)which was used directly in the next step.

NaBH₄ (54.4 g, 1.44 mol) was added portion-wise over 30 mins to a 0° C.solution of compound 3 (52 g, 86.4 mmol) and ethanol (600 mL). Thereaction mixture was extremely exothermic and great care was exercisedduring the addition of reducing agent. After the addition was complete,the reaction mixture was heated to reflux for 1 hour. The solution wascooled to ambient temperature and the reaction mixture solidified. Thesolid was broken-up to a slurry, which was then poured into brine (250mL). The resulting mixture was filtered and the filtrate wasconcentrated in vacuo. The resulting residue was vigorously stirred withether (200 mL×5). The ether layers were successively decanted from theresidue. The combined ether extracts were dried over magnesium sulfate,filtered, and the filtrate was concentrated in vacuo giving compound 4as white solid (25.2 g, yield 68%).

t-Butyldiphenylchlorosilane (31.9 mL, 0.123 mol) was added to a solutionof compound 4 (25.2 g, 0.123 mol), diisopropylethylamine (42.8 mL, 0.245mol), and CH₂Cl₂ (500 mL). The reaction solution was stirred at ambienttemperature for 24 hrs. The reaction solution was then washed with 0.5 NHCl (150 mL×3) and brine (150 mL). The organic layer was dried overmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The resulting residue was purified by flash chromatography (silica gel,4:1 hexanes:EtOAc) to give compound 5 (42 g, yield 77%).

Iodine (24 g, 94.7 mmol) was added portion-wise over 15 mins to a 0 Csolution of compound 5 (28 g, 63.1 mmol), Ph₃P (24.8 g, 94.7 mmol),imidazole (6.4 g, 94.7 mmol), diethyl ether (450 mL) and acetonitrile(150 mL). The ice bath was removed and the reaction solution was allowedto warm to ambient temperature over 30 mins. The reaction was judgedcomplete by TLC analysis (4:1 hexanes:EtOAc). The reaction was quenchedwith water (400 mL). The layers were separated and the aqueous layer wasextracted by diethyl ether (100 mL). The combined organic layers werewashed with saturated aqueous Na₂SO₃ (100×2) and brine (100 mL). Theorganic layer was dried over magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo. The resulting residue was purifiedby flash column chromatography (silica gel, 4:1 hexanes:EtOAc) to givecompound 6 (32 g, 92%).

Example 81

To a 0° C. solution of D-Aspartic acid 1 (59 g, 0.376 mol) in methanol(200 mL) was bubbled HCl gas for 10 minutes. After stirring at RTovernight, the solvent was evaporated and the resulting residue driedunder vacuum to provide crude product 2 as its HCl salt (0.376 mol).

To a stirred solution of 2 (0.376 mol), DIEA (196 mL, 1.13 mol) and THF(200 mL) was added benzyl chloroformate (59.0 mL, 0.414 mol) dropwise.After the reaction solution was stirred at room temperature for 1 hr,the solution was concentrated on a rotovap. The residue was partitionedbetween sat. NaHCO₃ (300 mL) and dichloromethane and the aqueous phaseextracted with additional dichloromethane (100 mL×3). The combineddichloromethane layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to give product 3 (0.376 mol).

To a solution of 3 (0.376 mol) in THF (200 mL) and water (100 mL) wasadded lithium hydroxide (31.6 g, 0.752 mol) and the mixture stirred for2 hours. The reaction mixture was filtered through a silica gel plug(the pH of the filtrate was about 7) and concentrated. The residue wasdried under vacuum to give 4 (0.376 mol).

A solution of 4 (0.376 mol) and acetic anhydrate (200 mL) was stirredfor 1 hour, after which the reaction mixture was concentrated and theresidue dried under vacuum to give 5 (0.376 mol).

To a 0° C. solution of 5 (0.376 mol) in THF (1000 mL) was added sodiumborohydride (14.2 g, 0.376 mol) portionwise over 30 minutes and themixture stirred for an additional 3 h. HCl solution (4N) was thendropped into the reaction solution until the pH was about 2. Thesolution was concentrated to about a quarter of the starting volume,diluted with water (300 mL) and extracted by ethyl ether (200 mL×3). Thecombined ether layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The resulting residue was dissolved in benzene(300 mL) and TsOH (500 mg) was added. The reaction mixture was stirredat reflux 3 hr after which it was concentrated to about 100 mL. Ether(200 mL) was added, which caused precipitate to form, and this whitesolid 6 (57.5 g, 65% from 1) was removed by filtration, washed with someether and dried under vacuum.

To a solution of 6 (30.0 g, 0.128 mol) in methanol (200 mL) was addedtriethylamine (142 mL, 1.02 mol) and the mixture stirred overnight. Thereaction mixture was concentrated and the residue dried under vacuum togive 7 (LC-MS showed about 20% mol 6 was left) which was directly usedin the next step.

A 0° C. solution of compound 7 (0.128 mol), Ph₃P (50.4 g, 0.192 mol),imidazole (13.1 g, 0.192 mol) and dichloromethane (300 mL) was stirredfor 10 min. Iodine (48.7 g, 0.192 mol) was added portion-wise over 15minutes, and then the ice bath was removed and the reaction solutionstirred at room temperature over 1 hour. The solid was removed byfiltration, and the filtrate was washed with saturated aqueous Na₂SO₃(200 mL×2) and brine (200 mL). The organic layer was dried over sodiumsulfate, filtered, concentrated. The resulting residue was purified byflash silica gel column chromatography (hexanes:EtOAc 4:1 to 1:1) togive compound 8 (27.5 g, 59.2% from 6) as a white solid.

A mixture of zinc powder (Strem, 10.1 g, 0.154 mol) and DMF (15 mL) waspurged with nitrogen for 10 minutes after which was added 1,2dibromoethane (0.758 mL, 8.80 mmol). The mixture was heated with a heatgun for ˜2 minutes, cooled down for 5 minutes and heated with a heat gunagain, then cooled to room temperature. TMSCl (281 μL, 2.20 mmol) wasadded, the mixture was stirred for 30 minutes, and 8 (9.98 g, 26.5 mmol)was added. After 1 hour, LCMS showed complete consumption of 8. To theabove reaction solution was added aryl iodide 9 (7.50 g, 22.0 mmol),Pd₂(dba)₃ (50.4 mg, 0.55 mmol) and tri-o-tolylphosphine (670 mg, 2.20mmol). The reaction mixture was maintained at 50° C. for 1 hour whilemonitering its progress by LC-MS. When done, the reaction mixture wasdirectly loaded onto a silica gel plug and washed with hexanes:EtOAc(3:1 to 1:1) to give compound 10 (5.0 g, 49%).

Example 82

To an oven dried round-bottom flask, zinc powder (1753 mg, 27 mmol) wasadded followed by DMF (15 mL). The flask was capped and purged withnitrogen for 10 min. To the solution was added 1,2 dibromoethane (0.139mL, 1.6 mmol). The mixture was then heated using a heat gun for about 30seconds until gas began to evolve indicating the activation of the zinc.The mixture was allowed to cool while stirring for 1 min before it washeated again using a heat gun until gas evolved. The mixture was thenallowed to cool to room temperature, followed by the addition of TMSCl(0.042 mL, 0.33 mmol) and stirring for 30 min. Reagent A was thendissolved in DMF, bubbled with nitrogen, added to the zinc solution, andallowed to stir for 1 hour at room temperature. Bromide 4 (1.381 g, 4.5mmol) was dissolved in DMF, bubbled with nitrogen and then injected intothe solution, followed by the addition of Pd₂(dba₃) (102 mg, 0.11 mmol)and tri-o-tolylphospine (136 mg, 0.44 mmol). The mixture was bubbledwith nitrogen and held under nitrogen while stirring at roomtemperature. After 1 hour, the stirring solution was heated to 40° C.for 2 hours until complete consumption of starting material by TLC andLC/MS. The solution was quenched using brine and extracted five timeswith EtOAc. The combined organic layers were dried over sodium sulfateand concentrated. The crude product 5 was purified via columnchromatography using EtOAc:Hex 1:1 to obtain 2.0 g (70% yield) of pureproduct 5.

Example 83

To a solution of compound 6 (940 mg, 1.78 mmol) in THF (5 mL) was added4 M HCl in 1,4-dioxane (20 mL, 80 mmol). The resulting mixture wasstirred at room temperature for 1 hour. The solvents were evaporated,and the residue was thoroughly dried under high vacuum. Compound 7 (726mg, 1.78 mmol, quantitative yield) was characterized using LCMS (LRMS(MH) 373 m/z) and used in the following step without furtherpurification.

To a solution of compound 7 (662 mg, 1.62 mmol) in DMF (5 mL) was addedDIEA (930 μL, 5.34 mmol) and compound 8 (678 mg, 1.78 mmol). Theresulting solution was stirred at room temperature for 1 hour. The DMFwas evaporated under vacuum, and the crude residue was purified usingpreparative reverse phase HPLC to provide compound 9 (435 mg, 0.77 mmol,48% yield), which was characterized by ¹H NMR and LC/MS (LRMS (MH) 569m/z.)

Compound 9 (100 mg, 0.176 mmol) was combined with HATU (134 mg, 0.352mmol), HOAT (48 mg, 0.352 mmol) and NH₄Cl (50 mg, 0.944 mmol). Thesolids were dissolved in N-methylpyrrolidinone (5 mL) and DIEA was added(93 μL, 0.528 mmol). The resulting mixture was stirred at roomtemperature for 2 hours and then loaded onto a preparative reverse phaseHPLC to provide compound 10 (16 mg, 0.028 mmol, 16% yield) as a glassysolid which was characterized by ¹H NMR and LC/MS (LRMS (MH) 568 m/z.)

Compound 9 (91 mg, 0.160 mmol) was combined with HBTU (121 mg, 0.320mmol) and HOBt (43 mg, 0.320 mmol). The solids were dissolved in DMF (3mL), and dimethylamine (400 μL, 0.800 mmol, 2 M in THF) and DIEA (93 μL,0.528 mmol) were added. The resulting solution was stirred at roomtemperature for 2 hours. The crude product was loaded onto a preparativereverse phase HPLC to provide compound 11 (25 mg, 0.042 mmol, 26% yield)as a glassy solid which was characterized by ¹H NMR and LC/MS (LRMS (MH)596 m/z.)

To a 0° C. solution of 1 (40.2 g, 117 mmol) in THF (250 mL) arid DIEA(11.4 mL, 175 mmol) was added isobutyl chloroformate (21.2 mL, 163mmol). The resulting mixture was stirred at room temperature for 3hours. The reaction was purged with gaseous ammonia for 1 hour and thenstirred at room temperature for 16 hours. It was diluted with water (200mL) and ethyl acetate (200 mL) and filtered. The white, filtered solidwas the desired product. Additional product was obtained by transferringthe biphasic filtrate to a separatory funnel and separating the layers.The aqueous phase was extracted with additional ethyl acetate (3×150mL). The organic phases were combined, dried (Na₂SO₄) and concentratedto a white solid, which was recrystallized from ethyl acetate to affordthe desired product. The pure product 2 (20.6 g, 60 mmol) wascharacterized by ¹H-NMR and LC/MS (LRMS (MH) m/z: 343.1).

Amide 2 (18.1 g, 53 mmol) was suspended in 1,4-dioxane (200 mL) andpyridine (10.7 mL, 132 mmol). Trifluoroacetic anhydride (22.0 mL, 158mmol) was added, and the white, suspended solid immediately dissolved.The homogeneous solution was stirred at room temperature for 30 minutes.The solvents were removed under reduced pressure, and the remainingresidue was dissolved in ethyl acetate (200 mL) and washed with 1 Maqueous KHSO₄ (2×100 mL) and saturated aqueous NaHCO₃ (2×100 mL). Theorganic phase was dried over Na₂SO₄ and concentrated in vacuo. Theremaining, desired product 3 (14.9 g, 46 mmol) was determined to besufficiently pure for the next transformation (LC/MS (LRMS (MH) m/z:198.0)).

Nitrile 3 (14.9 g, 46 mmol) was dissolved in 1,4-dioxane (100 mL) andtributyl (1-ethoxyvinyl)tin (23.3 mL, 69 mmol) was added, followed byPd(PPh₃)₂Cl₂ (1.6 g, 5 mol %). The resulting mixture was heated to 90 □Cand stirred for 4 hours. It was cooled to room temperature and thesolvent was removed under reduced pressure. The remaining residue waspurified using silica gel which was prepared in a slurry using 95%hexane/triethylamine. Elution was stepwise, beginning with 95%hexane/triethylamine and changing to 50% ethyl acetate/hexane/5%triethylamine. The desired product 4 eluted with the latter mobile phaseand was a viscous yellow oil, characterized by LC/MS (LRMS (MH) m/z:317.1). The product was used immediately in the next transformation.

To a solution of vinyl ether 4 (14.5 g, 46 mmol) in THF (60 mL) andwater (20 mL) was added N-bromosuccinimide (12.3 g, 69 mmol). Theresulting mixture was stirred at 50 □C for 30 minutes. It was cooled toroom temperature and diluted with 2 M aqueous Na₂CO₃. The mixture wasextracted with ethyl acetate (2×150 mL), and the organic extracts werecombined, dried over Na₂SO₄ and concentrated to an amorphous solid whichwas purified using silica gel (dichloromethane/ethyl acetate). Thedesired product 5 (10.6 g, 29 mmol) was a yellow solid, characterized by¹H-NMR and LC/MS (LRMS (MH) m/z: 239.9).

A solution of ketone 5 (10.6 g, 29 mmol) in 1,4-dioxane (50 mL) wasdripped into a solution of methylamine (72 mL, 144 mmol, 2 M in THF)over 45 minutes at 0 □C. The resulting cloudy solution was stirred foran additional 15 minutes at room temperature. The THF and methylaminewere evaporated under reduced pressure, and care was taken not toevaporate 1,4-dioxane. To the resulting mixture at room temperature wasadded triethylamine (12 mL, 87 mmol), followed by trimethylacetylchloride (15 mL, 144 mmol). The resulting suspension was stirred at toomtemperature for 30 minutes. It was diluted with water (125 mL) andextracted with ethyl acetate (3×100 mL). The organic phases werecombined, dried over Na₂SO₄ and concentrated in vacuo. The crude product6 was characterized by LC/MS (LRMS (MH) m/z: 402.1) and carried forwardwithout further purification.

Amide 6 (11.6 g. 29 mmol) was combined with ammonium acetate (55 g, 723mmol) and formamide (150 mL). The resulting mixture was heated to 100 □Cand stirred for 3 hours. It was cooled to room temperature, diluted withethyl acetate (500 mL) and washed with water (3×200 mL). The organicphase was dried over Na₂SO₄ and concentrated under reduced pressure. Theremaining crude residue was purified using silica gel (diethylether/hexane) to provide pure 7 (6.1 g, 16 mmol) as a foamy yellowsolid, characterized by ¹H-NMR and LC/MS (LRMS (MH) m/z: 383.2).

Imidazole 7 (1.316 g, 3.4 mmol) was combined with hydroxylaminehydrochloride (478 mg, 6.9 mmol) and dissolved in a solution of sodiummethoxide in methanol (14 mL, 6.9 mmol, 0.5 M). The resulting solutionwas stirred at 50 □C for 4 hours. It was concentrated under reducedpressure and purified using silica gel (5% methanol/dichloromethane) toprovide the desired amidoxime 8 (913 mg, 2.2 mmol) as a white solid,characterized by LC/MS (LRMS (MH) m/z: 416.1).

To a solution of amidoxime 8 (652 mg, 1.6 mmol) in methanol (10 mL) wasadded Raney nickel (50 mg) and acetic acid (250 μL). The mixture wasstirred at room temperature under 60 psi H₂ for 3 hours and thenfiltered through a bed of Celite®. Concentration under reduced pressureprovided pure amidine 9 as a white solid (638 mg, 1.6 mmol),characterized using LC/MS (LRMS (MH) m/z: 400.2).

Chloroacetaldehyde (360 mL, 5.7 mmol) was added to a solution of amidine9 (283 mg, 0.71 mmol) in DMF (4 mL) and K₂CO₃ (195 mg, 1.4 mmol). Themixture was heated to 50 □C and stirred for 4 hours. The reaction wasfiltered, directly loaded onto a reverse-phase HPLC and run with amobile phase gradient consisting of acetonitrile and water. The pureproduct 10 (25 mg, 0.06 mmol) was a glassy solid characterized by ¹H-NMRand LC/MS (LRMS (MH) m/z: 424.1).

To a solution of amidoxime 8 (148 mg, 0.35 mmol) intrimethylorthoacetate (5 mL) was added glacial acetic acid (100 μL). Theresulting solution was stirred at 65 □C for 16 hours. The solvents wereevaporated and the residue was directly purified through silica gel (5%methanol/dichloromethane) to provide the desired product 9 as a glassysolid, characterized by LC/MS (LRMS (MH) m/z: 440.1.

To a solution of 1 (200 mg, 0.5 mmol) in THF (3 mL) were added Bu₃P (150uL, 0.6 mmol) and 2-nitrophenylselenocyanate (136 mg, 0.6 mmol) at roomtemperature. The reaction mixture was stirred for 14 h. The mixture waspartitioned between EtOAc (200 mL) and H₂O (50 mL). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated. Theresulting residue was used without further purification. LRMS (M+H⁺) m/z587.1.

To a solution of 2 (˜0.5 mmol) in dichloromethane (5 mL) were addedaqueous KH₂PO₄ (2 M, 1 mL) and MCPBA (77%, 135 mg, 0.6 mmol). Theresulting mixture was stirred for 6 h and then quenched with saturatedNa₂S₂O₃ (10 mL). The organic layer was washed with saturated NaHCO₃,H₂O, and brine, dried over Na₂SO₄, and concentrated. The residue waspurified by RP—HPLC using a mixture of acetonitrile and H₂O to give 3(150 mg, 65% from 1). LRMS (M+H⁺) m/z 384.2.

To a solution of 3 (150 mg, 0.39 mmol) in dichloromethane (8 mL) wasadded TFA (1 mL). The reaction mixture was stirred for 4 h. The mixturewas concentrated, and dried under high vacuum. To the resulting residue(90 mg, 0.32 mmol) in THF (4 mL) were added DIEA (165 uL, 0.95 mmol) and4 (140 mg, 0.38 mmol). The resulting mixture was stirred for 14 h. Thereaction mixture was concentrated under vacuum and the residue purifiedby RP—HPLC using a mixture of acetonitrile and H₂O to give 5 (120 mg,65%). LRMS (M+H⁺) m/z 471.2.

To a solution of 5 (90 mg, 0.19 mmol) in THF/H₂O (2 mL/2 mL) were addedOsO₄ (4.8 mg, 0.019 mmol), NMO (117 mg, 0.95 mmol) and pyridine (1.5 uL,0.019 mmol). The resulting mixture was stirred for 6 h. NaHSO₃ (300 mg)was added. The reaction mixture was concentrated, and the resultingsolid was triturated with EtOAc (100 mL×3). The filtrate wasconcentrated and purified on a preparative TLC plate (silica gel, 5:1EtOAc/MeOH) to give diasteroisomers 6a (23 mg, 24%) and 6b (2 mg, 2%).LRMS (M+H⁺) m/z 505.2.

To a solution of amine 1 (150 mg, 0.309 mmol), dichloromethane (2 mL)and DIEA (53.8 uL, 0.309 mmol) was added acetyl chloride (53.8 uL, 0.309mmol). The resulting solution was stirred at room temperature for 10minutes. The solvent was evaporated, and the remaining residue waspurified by reverse phase Prep-HPLC (acetonitrile/water) to provide 2(43.7 mg, 26.8%). MS (MW+1): 527.2

To a solution of amine 1 (150 mg, 0.309 mmol), dichloromethane (2 mL)and DIEA (53.8 uL, 0.309 mmol) was added trimethylsilyl isocyanate (35.6uL, 0.309 mmol). The resulting solution was stirred at room temperatureovernight. The solvent was evaporated, and the remaining residue waspurified by reverse phase Prep-HPLC (acetonitrile/water) to provide 3(30.3 mg, 18.6%). MS (MW+1): 528.2

To a solution of amine 1 (150 mg, 0.309 mmol), dichloromethane (2 mL)and DIEA (53.8 uL, 0.309 mmol) was added methanesulfonyl chloride (24uL, 0.309 mmol). The resulting solution was stirred at room temperaturefor 30 minutes. The solvent was evaporated, and the remaining residuewas purified by reverse phase preparative HPLC (acetonitrile/water) toprovide 4 (18.4 mg, 10.6%). MS (MW+1): 563.1

Example 90

To a solution of amine 1 (150 mg, 0.309 mmol), dichloromethane (2 mL)and DIEA (53.8 uL, 0.309 mmol) was added methyl chloroformate (24 uL,0.309 mmol). The resulting solution was stirred at room temperature for30 minutes. The solvent was evaporated, and the remaining residue waspurified by reverse phase prep-HPLC (acetonitrile/water) to provide 5(CK1828648) (25.7 mg, 15.3%). MS (MW+1): 543.1

Example 91

80 mg (0.031 mmol) of(S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamidein 2 mL of pyridine was treated with 27.6 mg (0.033 mmol) ofhydroxylamine methyl ether hydrochloride. The reaction was stirredovernight after which the solvents were evaporated and the residuepurified via reverse phase HPLC (acetonitrile/water). 11.2 mg (70%yield) of 2 was obtained and characterized by LCMS and HNMR.

Example 92

100 mg (0.21 mmol) of(S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamidein 2 mL of pyridine was treated with 71.8 mg (1.0 mmol) of hydroxylaminehydrochloride. The reaction was stirred overnight after which thesolvents were evaporated and the residue purified via reverse phase HPLC(acetonitrile/water). 69.7 mg (67% yield) of 3 was obtained andcharacterized by LCMS and HNMR.

Example 93

150 mg (0.31 mmol) of(S)-N-(1-(4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamidein 2 mL of benzene was treated with 34.6 uL (0.62 mmol) ofethane-1,2-diol and 59 mg (0.31 mmol) of p-toluenesulfonic acidmonohydrate. The reaction was stirred at 70° C. for 2 h after which thesolvents were evaporated and the residue purified via reverse phase HPLC(acetonitrile/water). 25.5 mg (16% yield) of 4 was obtained andcharacterized by LCMS and HNMR.

Example 94

To a solution of 1 (1.5 g, 2.29 mmol), in ethanol (5.0 mL) was addedNaOH in water (1.0 M, 3.7 mL, 2.80 mmol). The reaction mixture wasstirred at ambient temperature for 2 hours. After the reaction was doneit was concentrated to give 2 (1.49 g) which was used directly in thenext step without further purification.

To a solution of 2 (1.49 g, 2.29 mmol), HBTU (1.3 g, 3.44 mmol), HOBt(530 mg, 3.44 mmol), and N,O-dimethylhydroxylamine HCl salt (340 mg,3.44 mmol) in DMF (20 mL) was added DIEA (785 uL, 4.58 mmol). Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated. The resulting residue was purifiedusing silica gel (Hexanes/EtOAc=1:3) to give pure compound 3 (1.20 g,78%) as an off-white, foamy solid.

To a 0° C. solution of 3 (1.20 g, 1.79 mmol) in anhydrous THF (20 mL)was added methylmagnesium bromide (3 M in Et₂O, 2.38 mL). The reactionmixture was stirred at 0° C. for 1 hour. The reaction mixture wasquenched with saturated NH₄Cl (5 mL) and water (20 mL). EtOAc (50 mL)was added, and the layers were separated. The aqueous phase wasextracted with additional EtOAc (50 mL×2) and the organic phases werecombined, dried (Na₂SO₄) and concentrated to a crude oil which waspurified using silica gel (50% EtOAc/hexanes). The desired compound 4(0.82 g, 73%) was a viscous oil which became a white foamy solid whiledrying under high vacuum.

To a solution of 4 (0.82 g, 1.31 mmol) in methanol (10 mL) was added HCl(4 M in 1,4-dioxane, 20 mL). The reaction was stirred at roomtemperature overnight. The mixture was concentrated and dried under highvacuum to give 5, which was used in the following step without furtherpurification.

To a solution of 5 (350 mg, 1.09 mmol) in DMF (5 mL) was added DIEA (280uL, 1.63 mmol) and ester H (472 mg, 1.09 mmol). The resulting solutionwas stirred at room temperature for 1 hour. The crude solution wasfiltered and then purified by reverse phase chromatography (using amixture of acetonitrile and water) to provide 6 as a foamy white solid(400 mg, 68%). LRMS (M+H⁺) m/z 538.1.

Ester 7 (10.2 g, 24.5 mmol) was dissolved in EtOH (150 mL) and water (50mL). Postassium hydroxide (4.1 g, 73.5 mmol) was added, and the reactionwas stirred at room temperature overnight. The reaction mixture wascooled to 0° C. and neutralized with concentrated HCl. Great care wastaken to not allow the pH to become <7 during the neutralization. Thesolvents were evaporated in vacuo, and the residue was dried under highvacuum. Acid 8 (9.5 g, 24.5 mmol) was used in the next step withoutfurther purification.

Acid 8 (9.5 g, 24.5 mmol) was combined with HBTU (18.5 g, 48.7 mmol),HOBt (6.6 g, 48.7 mmol), and N,O-dimethylhydroxylamine HCl (4.8 g, 48.7mmol). To the solids were added DMF (150 mL) and DIEA (12.7 mL, 73.1mmol). The resulting mixture was stirred at room temperature for 4hours. Most of the DMF was evaporated, and the remaining residue wasdiluted with ethyl acetate (300 mL) and water (300 mL). The layers wereseparated, and the aqueous phase was extracted with EtOAc (1×200 mL).The organic phases were combined, washed with saturated aqueous sodiumbicarbonate (2×250 mL), and dried over Na₂SO₄. Concentration underreduced pressure provided crude amide 9 which was purified using silicagel (3% MeOH/DCM) to give pure amide 9 (6.73 g, 17.4 mmol) as anoff-white, foamy solid.

A solution of amide 9 (6.73 g, 17.4 mmol) in anhydrous THF (250 mL) wascooled to 0° C. with an ice bath. Methylmagnesium bromide (3 M indiethyl ether, 52.2 mL, 156.6 mmol) was added, and the reaction wasstirred at 0° C. for 15 minutes. The reaction was carefully quenchedwith saturated ammonium chloride solution (20 mL) and water (100 mL).EtOAc (200 mL) was added, and the layers were separated. The aqueousphase was extracted with additional EtOAc (2×200 mL). The organic phaseswere combined, dried (Na₂SO₄) and concentrated to a crude oil which waspurified using silica gel (50% EtOAc/hexanes). The desired ketone 10(4.45 g, 11.5 mmol) was a viscous oil which became a white foamy solidwhile drying under high vacuum.

Ketone 10 (4.45 g, 11.5 mmol) was dissolved in THF (25 mL) and 4 M HClin 1,4-dioxane was added (75 mL). The reaction was stirred at roomtemperature for 1.5 hours. The solvents were evaporated in vacuo, andthe residue was thoroughly dried under high vacuum to provide amine 11.Amine 11 was used in the following step without further purification.

To a solution of amine 11 (3.30 g, 11.5 mmol) in DMF (50 mL) was addedDIEA (8.0 mL, 46.0 mmol) and ester H (5.25 g, 13.8 mmol). The resultingsolution was stirred at room temperature for 1 hour. Most of the DMF wasevaporated, and the remaining residue was diluted with EtOAc (250 mL)and water (200 mL). The layers were separated, and the organic phase waswashed with additional water (2×150 mL) and brine (2×150 mL). Theorganic phase was dried (Na₂SO₄) and concentrated. The remaining crude,viscous oil was purified using silica gel (100% EtOAc) to provide 12 asa foamy white solid (2.98 g, 6.2 mmol).

To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane.(400 mL) was slowly added trimethyloxonium tetrafluoroborate (13.1 g, 89mmol) at 0° C. After 10 min the ice bath was removed, and the reactionmixture was stirred overnight. The solvent was removed to give 18.0 g ofproduct 2 as a white solid, which was used without further purification.

A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol),sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) andcompound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C.until TLC showed no compound 2 left (about 2 h). The reaction mixturewas carefully neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate. The organic solution was dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography (EtOAc:Hex1:1) gave product 4 (9.11 g, 79%) as a white solid.

To a solution of compound 4 (3.174 g, 10.8 mmol) in DMF (15 mL) wasadded K₂CO₃ (4.478 g, 32.4 mmol) and(2-bromoethoxy)-tert-butyldimethylsilane (2.780 mL, 13.0 mmol). Theresulting mixture was stirred at 55° C. overnight. The solution wasconcentrated, diluted with water and extracted with EtOAc (3×50 mL). Theorganic layers were combined and dried over Na₂SO₄. The solvent wasremoved to give 7 as a viscous oil (4.805 g, 10.6 mmol, 98.4%), whichwas used in the subsequent step without further purification.

To a solution of compound 7 (2.174 g, 4.8 mmol) in anhydrous THF (25 mL)was added dropwise methylmagnesium bromide (4.8 mL, 3 M in diethylether, 14.4 mmol) under nitrogen at 0° C. The reaction was stirred at 0°C. for 15 minutes. The reaction was carefully quenched with saturatedammonium chloride solution (5 mL) and water (30 mL) and extracted withEtOAc (3×50 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated to a crude oil. Purification by flash column chromatography(15% EtOAc/Hex) gave the desired product 8 (1.371 g, 65%) as a whiteamorphous solid.

To a solution of compound 8 (1.371 g, 3.1 mmol) in THF (5 mL) was added35 mL of HCl (4 M in 1,4-dioxane). The resulting solution was stirred atroom temperature overnight. The solvents were removed to give product 9(1.0 g, 99%) as a white solid.

A mixture of compound 8 (0.5 g, 1.54 mmol) and 1 mL of TFA in toluene(60 mL) was refluxed overnight. The solid 8 did not dissolve untilaround the boiling point of toluene. The solvent was removed undervacuum. The residue was diluted with EtOAc, washed with NaHCO₃ aqueoussolution, dried over Na₂SO₄, and concentrated. Purification by flashcolumn chromatography (EtOAc:Hex 1:1) gave product 9 (0.348 g, 74%) as awhite solid.

To a suspension of zinc powder (255 mg, 3.9 mmol) in dry degassed DMF(15 mL) was added 1,2-dibromoethane (0.020 mL, 0.23 mmol) undernitrogen. The mixture was heated using a heat gun for about 30 secondsuntil gas started to evolve from the solution, indicating the activationof the zinc. The mixture was then allowed to cool to room temperaturefollowed by the addition of TMSCl (6 uL, 0.05 mmol), followed bystirring at room temperature for 30 min. A solution of iodo compound Ain degassed DMF was added to the zinc solution, and the reaction mixturewas stirred for 1 hour at room temperature. A solution of compound 9(200 mg, 0.65 mmol) in degassed DMF was then added via syringe, followedby the addition of Pd₂(dba₃) (14.9 mg, 0.016 mmol) andtri-o-tolylphospine (19.8 mg, 0.065 mmol). The reaction mixture wasstirred for one hour at room temperature and at 40° C. for 2 hours. Thereaction was complete as shown by TLC. The solution was quenched withbrine and extracted with EtOAc (5×50 mL). The combined organic layerswere dried over sodium sulfate and concentrated. Purification with flashcolumn chromatography (EtOAc:Hex 1:1) gave the product 10 (373 mg, 88%)as a colorless oil.

To a solution of compound 10 (373 mg, 0.57 mmol) in MeOH (10 mL) wasadded 2 mL of HCl (4.0 M in dioxane). The solution was allowed to stirat room temperature for 2 hours. The solvent was removed to give thecrude product 9 (180 mg, 99%), which was used without furtherpurification.

A mixture of compound 11 (180 mg, 0.57 mmol) and ester reagent B (260mg, 0.68 mmol) in DMF (10 mL) containing triethylamine (0.24 mL, 1.71mmol) was stirred at room temperature overnight. The reaction solutionwas diluted with brine and extracted with EtOAc (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated.Purification by reverse phase preparative HPLC (C18 column) gave theproduct 12 (141 mg, 50%) as a white solid.

To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added asolution of 3 (1.9 g, 6.5 mmol) in DMF (10 mL) at 0° C. under nitrogen.The reaction was stirred for 1.5 h, and then(2-bromoethoxy)-tert-butyldimethylsilane (2.09 mL, 9.7 mmol) was added.The reaction mixture was stirred overnight, diluted with EtOAc, quenchedwith aqueous ammonium chloride solution, and extracted with EtOAc (3×50mL). The organic layers were combined and dried over Na₂SO₄.Purification with over silica gel (EtOAc) gave the product 4 (1.2 g,41%) as a light yellow solid.

To a suspension of zinc powder (1.2 g, 18.4 mmol) in dry degassed DMF(15 mL) was added 1,2-dibromoethane (0.13 mL, 1.5 mmol) under nitrogen.The mixture was heated using a heat gun for about 30 seconds until gasstarted to evolve from the solution, indicating the activation of thezinc. The mixture was then allowed to cool to room temperature followedby the addition of TMSCl (100 uL), and allowed to stir at roomtemperature for 30 min. A solution of iodo compound A (1.71 g, 3.1 mmol)in degassed DMF was added to the zinc solution, and the reaction mixturewas stirred for 1 hour at room temperature. A solution of compound 4(1.0 g, 2.2 mmol) in degassed DMF was then added via syringe, followedby the addition of Pd₂(dba₃) (0.14 g, 0.015 mmol) andtri-o-tolylphospine (0.18 g, 0.06 mmol). The reaction mixture wasstirred for one hour at room temperature, and then at 60° C. overnight.The solution was quenched with brine and extracted with EtOAc (5×50 mL).The combined organic layers were dried over sodium sulfate andconcentrated. Purification with flash column chromatography (EtOAc:Hex1:1) gave the product 13 (346 mg, 20%) as a colorless oil.

To a solution was compound 13 (346 mg) in MeOH (10 mL) was added 2 mL ofHCl (4.0 M in dioxane). The solution was allowed to stir at roomtemperature for 2 h. The solvent was removed under vacuum to give thecrude product 14, which was used in the next step without furtherpurification.

A mixture of compound 14 and ester reagent B (200 mg, 0.52 mmol) in DMF(10 mL) containing triethylamine (0.15 mL, 1.08 mmol) was stirred atroom temperature overnight. The reaction solution was diluted withbrine, extracted with EtOAc (3×50 mL), and the combined organic layerswere dried over sodium sulfate and concentrated. Purification by reversephase preperative HPLC (C18 column) gave the product 8 (0.2 g, 87%) aswhite solid, and the lactone product 9 (15.4 mg, 7.3%) as white solid.LC-MS (CI) m/z 489.1 (MH⁺)

To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane(400 mL) was slowly added trimethyloxonium tetrafluoroborate (13.1 g, 89mmol) at 0° C. After 10 min the ice bath was removed, and the reactionmixture was stirred overnight. The solvent was removed to give 18.0 g ofproduct 2 as a white solid, which was used without further purification.

A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol),sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) andcompound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C.until TLC showed no compound 2 left (about 2 h). The reaction mixturewas carefully neutralized with saturated NaHCO₃ solution and extractedwith ethyl acetate. The organic solution was dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography (EtOAc:Hex1:1) gave product 4 (9.11 g, 79%) as a white solid.

To a solution of compound 4 (5.307 g, 18 mmol) in DMF (15 mL) was addedK₂CO₃ (3.73 g, 27 mmol) and iodoethane (3.5 mL, 43.2 mmol). Theresulting mixture was stirred at 60° C. for three hours. The mixture wasdiluted with water and extracted with EtOAc (3×50 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. Purificationwith column chromatography (Hex/EtOAc 50:50) gave product 6 (3.2 g, 55%)

To a suspension of zinc powder (3.90 g, 59.6 mmol) in dry degassed DMF(10 mL) was added 1,2-dibromoethane (308 uL, 3.58 mmol) under nitrogen.The mixture was heated using a heat gun for about 30 seconds until gasstarted to evolve from the solution, indicating the activation of thezinc. The mixture was then allowed to cool to room temperature followedby the addition of TMSCl (92 uL, 0.735 mmol), and allowed to stir atroom temperature for 30 min. A solution of iodo compound A (6.6 g, 11.9mmol) in degassed DMF was added to the zinc solution, and the reactionmixture was stirred for 1 hour at room temperature. Then a solution ofcompound 4 (3.2 g, 9.93 mmol) in degassed DMF was added via syringe,followed by the addition of Pd₂(dba₃) (223 mg, 0.244 mmol) andtri-o-tolylphospine (302 mg, 0.992 mmol). The reaction mixture wasstirred for one hour at room temperature, then at 60° C. for 2 hours.The reaction was complete as shown on TLC. The solution was quenchedwith brine and extracted with EtOAc (3×80 mL). The combined organiclayers were dried over sodium sulfate and concentrated. Purificationwith flash column chromatography (EtOAc:Hex 1:1) gave the product 5(5.43 mg, 82%) as a colorless oil.

To a solution of compound 5 (5.43 g, 8.1 mmol) in THF (50 mL) was addeddropwise a solution of MeMgBr bromide in ether (9.0 mL, 27 mmol) at 0°C. under nitrogen. The reaction was complete in 10 min via TLC. Thesolution was quenched by aqueous ammonium chloride solution while coldand extracted with EtOAc (3×60 mL). The combined organic layers weredried over sodium sulfate and concentrated. Purification with columnchromatography (Hexanes/EtOAc 1:1) gave the product 6 (4.86 g, 91%) ascolorless oil.

A mixture of compound 6 (4.86 g, 7.4 mmol), and 18 mL of HCl (4 M inDioxane) in MeOH (10.0 mL) was stirred at room temperature for 1 hour,followed by heating at 60° C. for 30 min. The reaction was complete viaTLC and LC/MS. The solvent was removed to give the product 7, which wasdirectly used for the next step.

A mixture of acid B (677 mg, 2.51 mmol), HBTU (3.6 g, 9.49 mmol), HOBT(1.45 g, 9.46 mmol) and DIEA (2.20 mL, 12.6 mmol) in DMF (40 mL) wasstirred at room temperature for 1 min followed by the addition of 7 (1.0g, 3.14 mmol). The reaction was complete in one hour via TLC and LC/MS.The solution was partitioned between EtOAc and brine, and extracted withEtOAc. The combined organic layers were dried over sodium sulfate andconcentrated under vacuum. Purification by HPLC gave product 8 (390 mg)as a white solid.

To a solution of 1 (10.7 g, 34.6 mmol) in MeOH/H₂O (60 mL/20 mL) wasadded NaOH (2 N, 20.8 mL, 41.6 mmol). After the mixture was stirred at50° C. for 2 h, the solution then was concentrated and under high vacuumto yield 10.3 g of light yellow solid (LRMS (M−H⁺) m/z 278.9), which wasused for the next step without further purification. To a solution ofthe crude mixture in DMF (50 mL) were successively addedN,O-dimethylhydroxylamine hydrochloride (4.0 g, 40.7 mmol), HBTU (4.0 g,40.7 mmol), HOBT (6.2 g, 40.7 mmol) and DIEA (6.0 mL, 40.7 mmol). Themixture was stirred at rt overnight. The solution then was partitionedbetween EtOAc and H₂O. The organic layer was washed with NaOH (1 N) andbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash column chromatography using a mixture of hexanes andEtOAc to give 2 (8 g, 72%). LRMS (M+H⁺) m/z 324.0.

To a solution of 2 (3.7 g, 11.4 mmol) in THF (40 mL) was added dropwiseMeMgBr in Et₂O (3M, 11.4 ml, 34.2 mmol) at 0° C. The mixture was stirredat 0° C. for 30 min. The solution was quenched with saturated NH₄Cl at0° C. and partitioned between EtOAc and H₂O. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated to give3 (3.0 g, 94%) which was taken on without further purification. LRMS(M+H⁺) m/z 279.0.

To a solution of 3 (3.0 g, 10.8 mmol) in THF/MeOH (10 mL/10 mL) wasslowly added NaBH₄ (407 mg, 10.8 mmol). The mixture was stirred for 10min, quenched by saturated NH₄Cl and partitioned between EtOAc and H₂O.The organic layer was washed with sat NaHCO₃ and brine, dried overNa₂SO₄, filtered and concentrated to give 4 (3.0 g, 99%), which was usedwithout further purification. LRMS. (M+H⁺) m/z 281.0.

To a solution of 4 (3.0 g, 10.7 mmol) in DMF (20 mL) was added TBDMSCl(1.6 g, 10.7 mmol), imidazole (726 mg, 10.7 mmol) and DMAP (271 mg, 21.3mmol). The mixture was stirred at rt overnight. The solution waspartitioned between EtOAc and H₂O and the organic layer washed with satNaHCO₃, H₂O, and brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash column chromatography over silica gelusing a mixture of hexanes and EtOAc to give 5 (3.5 g, 83%). LRMS (M+H⁺)m/z 395.1.

To a suspension of Zn (4.8 g, 74.4 mmol) in DMF (20 mL) was addedBrCH₂CH₂Br (320 μL, 3.7 mmol). The mixture was heated by heat gun for 4min. After the solution was cooled down, trimethylchlorosilane (95 μL,0.74 mmol) was added. After 30 min, Boc-□-iodo-Ala-OMe (5.2 g, 16.0mmol) was added, and reaction mixture was stirred at rt for 1 h. To thismixture were added Pd₂(dba)₃ (243 mg, 0.27 mmol), (O-Tol)₃P (269 mg,0.88 mmol) and 5 (3.5 g, 8.9 mmol). The mixture was heated at 50° C. for2 h, cooled down and filtered through Celite®. The solution waspartitioned between EtOAc and H₂O. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography using a mixture of hexanes and EtOActo give 6 (3.3 g, 72%). LRMS (M+H⁺) m/z 518.2.

To a solution of 6 (3.3 g, 6.4 mmol) in THF (20 mL) was slowly added LAH(1 M, 6.4 mL, 6.4 mmol) at 0° C. The mixture was stirred at 0° C. in 20min, and then quenched with H₂O (240 μL), NaOH (3 N, 240 μL), and H₂O(720 μL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatographyover silica gel using a mixture of hexanes and EtOAc to give 7 (1.57 g,50%). LRMS (M+H⁺) m/z 490.2.

To a solution of 7 (1.57 g, 3.2 mmol) in THF (20 mL) were added PPh₃(1.0 g, 3.9 mmol), DIAD (746 μL, 3.9 mmol) and phthalimide (567 mg, 3.9mmol). After the solution was stirred at rt for 4 hours the reaction wasjudged to be completed by LCMS, and the reaction was partitioned betweenEtOAc and H₂O. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography using a mixture of hexanes and EtOAc to give 8 (2.0 g,99%). LRMS (M+H⁺) m/z 619.2.

To a solution of 7 (2 g, 3.2 mmol) in MeOH (15 mL) was added NH₂NH₂(1.01 mL, 32.3 mmol). After the reaction was stirred at room temperaturefor about 4 h, the solution was precipitated, filtered, and the solidwashed with CH₂Cl₂ and methanol. The organic layer was concentrated togive 8 (2.5 g), which was used without further purification. LRMS (M+H⁺)m/z 489.2.

To a solution of 8 (1.5 g, 3.1 mmol) in CH₂Cl₂/CH₃CN (15 mL/15 mL) wereadded DIEA (588 μL, 3.4 mmol) and chloroacetyl chloride (269 μL, 3.4mmol). After the reaction was stirred at rt for 10 min, azetidine (2 mL,30.7 mmol) and DIEA (2.7 ml, 15.3 mmol) were added. The reaction mixturewas stirred overnight. The solution was concentrated and partitionedbetween EtOAc and H₂O, and the organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash column chromatography over silica gel using a mixture ofhexanes and EtOAc to give 9 (900 mg, 51%) LRMS (M+H⁺) m/z 586.3.

To a solution of 9 (900 mg, 1.53 mmol) in MeOH (1 mL) were added HCl indioxane (4 N, 2 mL) and HCl in H₂O (2 N, 1 mL). The solution was stirredat rt overnight and concentrated to give a white solid that was taken onto the next step. To a DMF (10 mL) solution of the crude compound wereadded 9.1 (665 mg, 1.53 mmol) and DIEA (800 uL, 4.59 mmol). The mixturewas stirred at rt for 1 h and partitioned between EtOAc and H₂O. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by reverse-phase HPLC to give 10(600 mg, 63%). LRMS (M+H⁺) m/z 622.2.

To a solution of 10 (160 mg, 0.24 mmol) in dichloromethane (10 mL) wasadded MnO₂ (416 mg, 4.8 mmol). The suspension was stirred for 14 h. Thereaction mixture was filtered, and the filtrate was concentrated andpurified by reverse-phase HPLC using a mixture of acetonitrile and H₂Oto give 11 (90 mg, 60%). LRMS (M+H⁺) m/z 620.1.

Example 98

The following compounds were prepared using the procedures describedabove: Name MS (m/z)N-(1-{4-[2-(1-Acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-498.1hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-{1-[4-(8-isopropenyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-555.2 propyl}-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-Acetylamino-propyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-541.2 hydroxy-propyl)-3-chloro-4-(isopropoxy)-benzamideN-[1-(4-{2-[1-(Acetyl-methyl-amino)-ethyl]-1-ethyl-1H-imidazol-4-yl}-555.2benzyl)-3-hydroxy-propyl]-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{4-[2-[1-(Acetyl-methyl-amino)-ethyl]-1-ethyl-1H-imidazol-4-yl]-546.2 benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-{1-[4-(8-Bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-555.3 3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-Acetylamino-ethyl)-1-isopropyl-1H-imidazol-4-yl]-benzyl}-595.2 3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-Acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-610.2hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(2-(2-dimethylamino-acetylamino)-1-{4-[8-methyl-imidazo[1,2- 489.2a]pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-Acetylamino-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]-629.2benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-{1-[4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-639.2 cyano-4-isopropoxy-benzamideN-(2-(2-dimethylamino-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)- 567.2imidazo[1,2-a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-amino-2-methyl-propionylamino)-1-{4-[8-bromo-imidazo[1,2- 527.2a]pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{3-fluoro-4-[2-(1-methyl-1hydroxy-ethyl)-1-ethyl-1H-imidazol-4-yl]-532.2 benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-{1-[2-fluoro-4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-528.2 propyl}-3-cyano-4-isopropoxy-benzamideN-{1-[4-(8-acetyl-5-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-569.2 propyl}-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-Acetylamino-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]-595.1 benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-t-butyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-503.3 cyano-4-isopropoxy-benzamideN-(2-(2-dimethylamino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-582.2 2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-carbamoyl- 512.1propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-isobutyryl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-514.3 propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-533.3 propyl)-3-cyano-4-isopropoxy-benzamideN-[1-[4-(8-Bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-(2-oxo-tetrahydro-568.2 pyrimidin-1-yl)-ethyl]-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-527.1 (Negative) 3-cyano-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-(2,2,2-trifluoroethyl)-1H- 541.2imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-[1-[4-(2-acetyl-1-ethyl-1H-imidazol-4-yl)-benzyl]-2-(2-hydroxy- 568.2acetylamino)-ethyl]-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-(2-methoxyethyl)-1H-imidazol-4-yl]-benzyl}-3- 528.2hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-amino-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-503.2 a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-512.2 3-cyano-4-isopropoxy-benzamideN-(1-{4-(8-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzyl}-511.1 3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-propyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-512.2 3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-484.1 3-chloro-4-isopropoxy-benzamideN-(2-(2-amino-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-582.2 yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]- 586.1benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{3-fluoro-4-[2-(1-hydroxy-1-methyl-ethyl)-1-ethyl-1H-imidazol-4-yl]-513.1benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-(2,2,2-trifluoroethyl)-1H- 559.2imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy- benzamideN-(1-{4-[2-(1-formylamino-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3-489.2 hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-527.1 a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-490.2 3-cyano-4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl- 505.2propyl}-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-502.1 3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-carbamoyl- 516.1propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{3-fluoro-4-[2-acetyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-498.1 propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-propionyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- 537.1propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-hydroxy-acetylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-499.1 benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(3-hydroxy-pent-3-yl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-542.3 hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-dimethylamino-acetylamino)-1-{4-[8-methyl-imidazo[1,2- 552.1a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl- 514.2propyl}-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxypropyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3- 497.1hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-hydroxy-acetylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-538.1 benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-526.2 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-514.2 carbamoyl-propyl}-3-chloro-4-isopropoxy-benzamideN-{1-[2-fluoro-4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-559.2 propyl}-3-chloro-4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-546.1 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-527.23-hydroxy-propyl)-3-cyano-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{2,3,5,6-tetrafluoro-4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-493.2 3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-568.1 3-chloro-4-isopropoxy-benzamideN-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-473.3 carbamoyl-propyl}-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-2-methyl-propyl)-1-ethyl-1H-imidazol-4-yl]- 500.2benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazol-4-yl]- 528.2benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-isopropyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- 512.2propyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-trifluoromethyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-512.2 propyl)-3-cyano-4-isopropoxy-benzamideN-(1-hydroxy-1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-phenyl}-4- 539.2hydroxy-butyl)-3-chloro-4-isopropoxy-benzamideN-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-(3-methyl-ureido)-491.2 ethyl]-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-methyl-1H-imidazol-4-yl]- 610.2benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-(3-methyl- 501.3ureido)-ethyl]-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-527.2 3-cyano-4-cyclobutoxy-benzamideN-(1-{4-[2-(methylsulfonyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3- 570.1hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-ureido-ethyl]-3-527.2 cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-1-methyl-1H-imidazol-4-yl]-513.1 benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-methyl-1H-imidazol-4-yl]- 554.1benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-568.2 yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-hydroxy-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-593.2 yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-552.1 2,3-dichhloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-547.1 chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-{1-[4-(5-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-474.2 3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-478.1 3-cyano-4-(isopropylamino)-benzamideN-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-622.2 2-amino-3-chloro-4-isopropoxy-benzamideN-{1-[4-(8-(1-methyl-1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)- 543.1benzyl]-3-hydroxy-propyl}-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-(1-(methoxycarbonylamino)-ethyl)-1-methyl-1H-imidazol-4-yl]-611.2 benzyl}-3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamideN-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-625.2 a]pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-{1-[4-(imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-511.2 4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-491.1 3-chloro-4-(isopropylamino)-benzamideN-(2-(3-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-513.3 yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-{1-[2,6-difluoro-4-(8-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-579.1 yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4-isopropoxy-benzamideN-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-(2-oxo- 556.2imidazolidinyl)-ethyl]-3-chloro-4-isopropoxy-benzamideN-[1-[4-(2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazol-4-yl)- 526.2benzyl]-2-(2-amino-propionylamino)-ethyl]-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-butyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-554.2 chloro-4-isopropoxy-benzamideN-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-2-475.5 carbamoyl-ethyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[4-t-butyl-1H-imidazol-2-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-503.3 4-isopropoxy-benzamideN-(2-(2-hydroxy-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-566.1 a]pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(1-{4-[2-isobutyryl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-518.2 propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamideN-(1-{4-[2-t-butyl-1-(2-aminoethyl)-1H-imidazol-4-yl]-benzyl}-3-hydroxy-513.1 propyl)-3-cyano-4-isopropoxy-benzamideN-(2-(2-dimethylamino-acetylamino)-1-{4-[8-carbamoyl-imidazo[1,2- 556.1a]pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(2-(2-amino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-513.2 benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamideN-(2-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-phenyl}-1-(5-methyl- 530.3[1,2,4]oxadiazol-3-yl)-ethyl)-3-cyano-4-isopropoxy-benzamideN-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-hydroxy-3-azido-489.2 propyl]-3-cyano-4-isopropoxy-benzamideN-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-498.1 hydroxy-propyl}-3-cyano-4-isopropoxy-benzamideN-(1-{4-[5-t-butyl-4-methyl-1H-imidazol-2-yl]-benzyl}-3-hydroxy-propyl)-581.1 3-chloro-4-isopropoxy-benzamideN-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-489.2 cyano-4-isopropoxy-benzamideN-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-483.2 yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamideN-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-475.5 3-chloro-4-isopropylamino-benzamide

Example 99

To a solution of 1 in DMF (158 mg, 0.41 mmol) were added amino acid 2(100 mg, 0.52 mmol) and DIEA (272 μL, 0.16 mmol). The reaction wasstirred for 14 h. Methylamine (2 M in THF, 0.4 mL) and HBTU (295 mg,0.78 mmol) were then added. The reaction mixture was stirred for 5 h.The product was purified by RP—HPLC using a mixture of acetonitrile andH₂O to give 3 (105 mg, 63%). LRMS (M+H⁺) m/z 401.1.

Example 100

To a solution of 1 (3 g, 16.4 mmol) in H₂O and conc. H₂SO₄ (100 mL/50mL) was added a solution of NaNO₂ (1.35 g, 19.7 mmol) in H₂O (10 mL)dropwise in 40 minutes at 0° C. After 15 minutes, the solution waswarmed to room temperature and added dropwise into a mixture of conc.H₂SO₄/H₂O (120 mL/180 mL) at 110° C. in 40 minutes. After the solutionwas cooled to room temperature, it was extracted with ethyl acetate(3×). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give 3 (1.3 g, 43%) as a crude red solid.LRMS (M−H⁺) m/z 181.9.

Compound 3 (1.3 g, 7.10 mmol), isopropyl bromide (3.3 mL, 35.5 mmol),and K₂CO₃ (3.9 g, 28.3 mmol) were mixed in DMF (10 mL) in a sealed tubeand heated to 80° C. for about 2 hours. The mixture was partitionedbetween EtOAc and water and the organic layer washed with brine, driedover Na₂SO₄ and concentrated to give crude brown oil 4 (2.2 g). To asolution of compound 4 (2.2 g, 8.23 mmol) in methanol (10 mL) and EtOAc(10 mL) was added Pd/C (350 mg), and the solution was stirred under astream of H₂ overnight. The solution was filtered through Celite® andconcentrated and the residue purified on silica gel to give 5 (1.3 g,66%).

A solution of compound 5 (1.23 g, 5.18 mmol) and N-chlorosuccinimide(692 mg, 5.18 mmol) in DMF (10 mL) was heated to 100° C. for 30 minutes.The mixture was partitioned between EtOAc and water and the organiclayer washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified on silica gel to give 6 (836 mg, 59% LRMS (M−H⁺) m/z 270.0)and 7 (563 mg, 40%, LRMS (M−H⁺) m/z 270.0).

To a solution of compound 6 (670 mg, 2.47 mmol) in MeOH and H₂O (6 ml/2mL) was added KOH (415 mg, 7.4 mmol). The mixture was heated to 50° C.for 4 hours and cooled down to room temperature. The solution then wasacidified to pH=3 and extracted by EtOAc (3×). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 8 (570 mg, quant.) without further purification.LRMS (M−H⁺) m/z 228.0.

To a solution of crude 8 (80 mg, 0.35 mmol) in DMF (1 mL) weresuccessively added compound 9 (118 mg, 0.35 mmol), HBTU (198 mg, 0.52mmol) and DIEA (303 μL, 1.74 mmol). The solution was stirred at roomtemperature for 1 hour and purified by RP—HPLC using a mixture ofacetonitrile and H₂O to give 10 (40 mg, 22%). LRMS (M+H⁺) m/z 513.2.

Example 101

methyl1-(4-biphenylylmethyl)-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)hydrazinecarboxylate

a) methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate

A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (1.00 g, 4.66mmol) in methanol (10.0 mL) was treated with SOCl₂ (0.68 mL, 9.32 mmol).After stirring overnight at ambient temperature, the solution wasconcentrated in vacuo and taken on without purification. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.04 (d, J=2.3 Hz, 1 H) 7.89 (dd, J=8.7, 2.1Hz, 1 H) 6.93 (d, J=8.6 Hz, 1 H) 4.66 (qq, J=6.1 Hz, 1 H) 3.88 (s, 3 H)1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 229 [M+H]⁺.

b) 3-chloro-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 101a) (˜1.065 g crude, 4.66mmol) in ethanol (1.5 mL) was treated with hydrazine monohydrate (1.13mL, 23.3 mmol). The reaction mixture was heated to reflux and stirredfor 3 h. Upon cooling, the solution was treated with H₂O, extractedthrice with EtOAc, dried over MgSO₄, filtered, and concentrated invacuo. Recrystallization from CH₂Cl₂ gave the title compound as whitecrystals (1.01 g; 95%, 2 steps). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm7.81 (d, J=2.3 Hz, 1 H) 7.63 (dd, J=8.6, 2.0 Hz, 1 H) 6.94 (d, J=8.6 Hz,1 H) 4.63 (qq, J=6.0 Hz, 1 H) 4.09 (br. s., 2 H) 1.40 (d, J=6.1 Hz, 6H). MS(ES+) m/e 229 [M+H]⁺.

c) 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-oxadiazol-2(3H)-one

A solution of the compound from Example 101b) (0.477 g, 2.09 mmol) intetrahydrofuran (8.0 mL) was treated with carbonyldiimidazole (0.379 g,2.29 mmol). The reaction mixture was heated to reflux and stirred for1.5 h. Upon cooling, the solution was concentrated in vacuo and purifiedvia flash column chromatography (10-40% EtOAc/hexanes) to yield thetitle compound as a white solid (0.515 g; 97%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.35 (s, 1 H) 7.87 (d, J=2.3 Hz, 1 H) 7.68 (dd,J=8.7, 2.1 Hz, 1 H) 6.99 (d, J=8.6 Hz, 1 H) 4.66 (qq, J=6.1 Hz, 1 H)1.42 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 255 [M+H]⁺.

d)3-(4-biphenylylmethyl)-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-oxadiazol-2(3h)-one

A solution of the compound from Example 101c) (0.170 g, 0.668 mmol) inCH₃CN (2.0 mL) was treated with 4-(bromomethyl)biphenyl (0.181 g, 0.734mmol) and K₂CO₃ (0.101 g, 0.734 mmol). The reaction mixture was heatedto 80° C. for 30 min. in a Biotage Initiator microwave synthesizer.Following cooling, the reaction mixture was treated with water andextracted thrice with CH₂Cl₂. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. Purification via flash columnchromatography (10-40% EtOAc/hexanes) gave the title compound as whitecrystals (0.256 g; 91%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (d,J=2.0 Hz, 1 H) 7.65 (dd, J=8.6, 2.3 Hz, 1 H) 7.60 (d, J=8.3 Hz, 2 H)7.55-7.61 (m, 2 H) 7.48 (d, J=8.3 Hz, 2 H) 7.44 (t, J=7.6 Hz, 2 H) 7.35(tt, J=7.4, 1.1 Hz, 1 H) 6.96 (d, J=8.8 Hz, 1 H) 4.97 (s, 2 H) 4.64 (qq,J=6.1 Hz, 1 H) 1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 421 [M+H]⁺.

e) methyl1-(4-biphenylylmethyl)-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)hydrazinecarboxylate

A solution of the compound from Example 101d) (0.101 g, 0.240 mmol) inmethanol (1.0 mL) and tetrahydrofuran (1.0 mL) was treated with 1Naqueous NaOH (1.0 mL). After stirring 1 h at ambient temperature, thereaction was quenched with 1N aqueous HCl, diluted with brine andextracted thrice with EtOAc. The organic solution was dried over MgSO₄,filtered, and concentrated in vacuo. Purification via flash columnchromatography (10-40% EtOAc/hexanes) gave the title compound as a whitesolid (0.101 g; 93%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.82 (s, 1 H)7.73 (d, J=2.0 Hz, 1 H) 7.50-7.61 (m, 5 H) 7.44 (t, J=7.6 Hz, 2 H)7.32-7.38 (m, 3 H) 6.89 (d, J=8.6 Hz, 1 H) 4.83 (s, 2 H) 4.59 (qq, J=6.1Hz, 1 H) 3.77 (s, 3 H) 1.38 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 453 [M+H]⁺.

1-(4-biphenylylmethyl)-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methylhydrazinecarboxamide

A solution of the compound from Example 101d) (0.050 g, 0.119 mmol) intetrahydrofuran (2.0 mL) was treated with methylamine (0.60 mL, 2.0 Msolution in tetrahydrofuran, 1.20 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.089 mL, 0.594 mmol). The solutionwas heated to 80° C. for 2.5 h in a Biotage Initiator microwavesynthesizer. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (0.089 mL,0.594 mmol) was added and the solution was heated to 80° C. for anadditional 2 h in a Biotage Initiator microwave synthesizer. Followingcooling, the reaction mixture was treated with water and extracted twicewith EtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. Purification via flash column chromatography(40-80% EtOAc/hexanes) gave the title compound as a white solid (0.044g; 82%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (d, J=2.0 Hz, 1 H)7.49-7.61 (m, 6 H) 7.43 (t, J=7.5 Hz, 2 H) 7.32-7.39 (m, 3 H) 6.90 (d,J=8.8 Hz, 1 H) 5.23 (br. s., 1 H) 4.88 (br. s., 2 H) 4.62 (qq, J=6.1 Hz,1 H) 2.83 (s, 3 H) 1.39 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 452 [M+H]⁺.

2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({4-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

a)5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-({4-[(phenylmethyl)oxy]phenyl}methyl)-1,3,4-oxadiazol-2(3H)-one

A solution of the compound from Example 101c) (0.150 g, 0.589 mmol) inCH₃CN (2.0 mL) was treated with 4-(benzyloxy)benzyl chloride (0.151 g,0.648 mmol) and K₂CO₃ (0.090 g, 0.648 mmol). The reaction mixture washeated to 100° C. for 30 min. in a Biotage Initiator microwavesynthesizer. Following cooling, the reaction mixture was treated withwater and extracted thrice with CH₂Cl₂. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (0-25% EtOAc/hexanes) gave the title compound as awhite solid (0.251 g; 95%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84(d, J=2.0 Hz, 1 H) 7.63 (dd, J=8.7, 1.9 Hz, 1 H) 7.26-7.48 (m, 7 H) 6.97(d, J=8.3 Hz, 2 H) 6.95 (d, J=8.3 Hz, 1 H) 5.06 (s, 2 H) 4.86 (s, 2 H)4.64 (qq, J=6.1 Hz, 1 H) 1.40 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 451[M+H]⁺.

b)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({4-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

Following the procedure of Example 102, except substituting the compoundfrom Example 103a) for the compound from Example 101d), the titlecompound was obtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 7.67 (d, J=2.0 Hz, 2 H) 7.54 (dd, J=8.6, 2.0 Hz, 1 H) 7.34-7.43 (m,4 H) 7.31 (tt, J=6.8, 1.8 Hz, 1 H) 7.19 (d, J=8.3 Hz, 2 H) 6.90 (d,J=8.3 Hz, 2 H) 6.89 (d, J=8.3 Hz, 1 H) 5.21 (br. s., 1 H) 5.02 (s, 2 H)4.75 (s, 2 H) 4.63 (qq, J=6.0 Hz, 1 H) 2.78 (s, 3 H) 1.39 (d, J=6.1 Hz,6 H). MS(ES+) m/e 482 [M+H]⁺.

2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

a) 3-(methoxy)-4-(benzyloxy)benzyl methanesulfonate

A solution of 3-(methoxy)-4-(benzyloxy)benzyl alcohol (0.244 g, 1.00mmol) in CH₂Cl₂ (2.0 mL) was treated with methanesulfonylchloride (0.085mL, 1.10 mmol) and Et₃N (0.160 mL, 1.15 mmol). After stirring 1 h atambient temperature, the reaction mixture was filtered through a shortplug of silica gel using CH₂Cl₂ as the eluant. The solution wasconcentrated in vacuo and taken on without purification. MS(ES+) m/e 323[M+H]⁺.

b)5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-({3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}methyl)-1,3,4-oxadiazol-2(3H)-one

Following the procedure of Example 101d), except substituting thecompound from Example 104a) for 4-(bromomethyl)biphenyl, the titlecompound was obtained as a viscous white oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.84 (d, J=2.3 Hz, 1 H) 7.63 (dd, J=8.7, 2.1 Hz, 1H) 7.40-7.45 (m, 2 H) 7.33-7.38 (m, 2 H) 7.29 (tt, J=7.2, 1.6 Hz, 1 H)6.96 (d, J=2.8 Hz, 1 H) 6.95 (d, J=4.3 Hz, 1 H) 6.90 (dd, J=8.3, 2.0 Hz,1 H) 6.85 (d, J=8.1 Hz, 1 H) 5.15 (s, 2 H) 4.84 (s, 2 H) 4.63 (qq,J=6.2, 6.0 Hz, 1 H) 3.90 (s, 3 H) 1.40 (d, J=6.1 Hz, 6 H). MS(ES+) m/e481 [M+H]⁺.

c)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

A solution of the compound from Example 104b) (0.120 g, 0.250 mmol) intetrahydrofuran (2.0 mL) was treated with methylamine (1.25 mL, 2.0 Msolution in tetrahydrofuran, 2.495 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.746 mL, 4.99 mmol). The solutionwas heated to 100° C. for 3 h in a Biotage Initiator microwavesynthesizer. Following cooling, the reaction mixture was treated withwater and extracted thrice with EtOAc. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (30-80% EtOAc/hexanes) gave the title compound asa white solid (0.093 g; 73%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69(d, J=2.3 Hz, 1 H) 7.52 (dd, J=8.6, 1.8 Hz, 1 H) 7.46 (s, 1 H) 7.41 (dd,J=8.4, 1.5 Hz, 2 H) 7.35 (tt, J=7.1, 1.6 Hz, 2 H) 7.29 (tt, J=7.2, 1.6Hz, 1 H) 6.89 (d, J=8.8 Hz, 1 H) 6.86 (s, 1 H) 6.80 (d, J=8.4 Hz, 1 H)6.71 (dd, J=8.2, 1.4 Hz, 1 H) 5.17 (br. s., 1 H) 5.12 (s, 2 H) 4.75 (br.s., 2 H) 4.64 (qq, J=6.1, 5.9 Hz, 1 H) 3.80 (s, 3 H) 2.80 (s, 3 H) 1.40(d, J=6.1 Hz, 6 H). MS(ES+) m/e 512 [M+H]⁺.

2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({4-[(phenylcarbonyl)amino]phenyl}methyl)hydrazinecarboxamide

a)5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-[(4-nitrophenyl)methyl]-1,3,4-oxadiazol-2(3H)-one

Following the procedure of Example 101d), except substituting4-nitrobenzylbromide for 4-(bromomethyl)biphenyl, the title compound wasobtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24(dt, J=8.8, 2.0 Hz, 2 H) 7.84 (d, J=2.3 Hz, 1 H) 7.64 (dd, J=8.6, 2.3Hz, 1 H) 7.57 (d, J=8.8 Hz, 2 H) 6.97 (d, J=8.8 Hz, 1 H) 5.02 (s, 2 H)4.65 (qq, J=6.1, 5.9 Hz, 1 H) 1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 390[M+H]⁺.

b)3-[(4-aminophenyl)methyl]-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-oxadiazol-2(3H)-one

A solution of the compound from Example 105a) (0.370 g, 0.954 mmol) intetrahydrofuran (2.0 mL) was treated with tin(II) chloride dihydrate(2.15 g, 9.54 mmol) and concentrated aqueous HCl (1.0 mL). Afterstirring 2 h at ambient temperature, the reaction mixture was pouredinto a 6N aqueous NaOH/ice mixture and extracted twice with EtOAc. Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuo.Purification via flash column chromatography (10-100% EtOAc/hexanes)gave the title compound as a light yellow solid (0.308 g; 90%). ¹H NMR(400 MHz, CD₃OD) δ ppm 7.80 (d, J=2.0 Hz, 1 H) 7.71 (dd, J=8.7, 2.1 Hz,1 H) 7.59 (d, J=8.3 Hz, 2 H) 7.43 (d, J=8.3 Hz, 2 H) 7.20 (d, J=8.8 Hz,1 H) 5.02 (s, 2 H) 4.77 (qq, J=6.1 Hz, 1 H) 1.38 (d, J=6.1 Hz, 6 H).MS(ES+) m/e 360 [M+H]⁺.

c)N-(4-{[5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]methyl}phenyl)benzamide

A solution of the compound from Example 105b) (0.110 g, 0.306 mmol) inCH₂Cl₂ (5.0 mL) was treated with benzoyl chloride (0.043 mL, 0.367 mmol)and Et₃N (0.051 mL, 0.367 mmol). After stirring 16 h at ambienttemperature, the reaction mixture was treated with water and extractedthrice with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered,and concentrated in vacuo to give the title compound as an off-whitesolid (0.136 g; 96%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H)7.85 (d, J=7.3 Hz, 2 H) 7.78 (d, J=2.0 Hz, 1 H) 7.68 (d, J=8.3 Hz, 2 H)7.59 (dd, J=8.6, 2.0 Hz, 1 H) 7.47 (t, J=7.3 Hz, 1 H) 7.39 (t, J=7.5 Hz,2 H) 7.34 (d, J=8.3 Hz, 2 H) 6.93 (d, J=8.8 Hz, 1 H) 4.86 (s, 2 H) 4.61(qq, J=6.1 Hz, 1 H) 1.38 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 464 [M+H]⁺.

d)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({4-[(phenylcarbonyl)amino]phenyl}methyl)hydrazinecarboxamide

Following the procedure of Example 104c), except substituting thecompound from Example 105c) for the compound from Example 104b), thetitle compound was obtained as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.53 (s, 1 H) 8.30 (s, 1 H) 8.18 (d, J=1.8 Hz, 1 H)7.98 (dd, J=8.7, 1.6 Hz, 1 H) 7.72 (d, J=7.8 Hz, 2 H) 7.46 (t, J=7.3 Hz,1 H) 7.36 (t, J=7.7 Hz, 2 H) 7.30 (d, J=8.1 Hz, 2 H) 6.91 (d, J=9.1 Hz,2 H) 6.88 (d, J=8.8 Hz, 1 H) 5.46 (q, J=4.8 Hz, 1 H) 4.74 (br. s., 2 H)4.57 (qq, J=6.0 Hz, 1 H) 2.79 (d, J=4.8 Hz, 3 H) 1.33 (d, J=5.8 Hz, 6H). MS(ES+) m/e 495 [M+H]⁺.

N²-{[2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-1-({4-[(phenylmethyl)oxy]phenyl}methyl)hydrazino]carbonyl}glycinamide

Following the procedure of Example 104c), except substituting glycinamdehydrochloride for methylamine and the compound from Example 103a) forthe compound from Example 104b), the title compound was obtained as anoff-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (s, 1 H) 7.71(s, 1 H) 7.55 (dd, J=8.6, 1.5 Hz, 1 H) 7.28-7.39 (m, 5 H) 7.15 (d, J=8.1Hz, 2 H) 6.87 (d, J=7.1 Hz, 3 H) 6.72 (s, 1 H) 6.22 (t, J=5.6 Hz, 1 H)5.63 (s, 1 H) 4.97 (s, 2 H) 4.64 (br. s., 2 H) 4.60 (qq, J=6.1 Hz, 1 H)3.74 (d, J=5.3 Hz, 2 H) 1.36 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 525 [M+H]⁺.

N′-(4-biphenylylmethyl)-3-chloro-N′-(hydrazinocarbonyl)-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 101d) (0.046 g, 0.109 mmol) intetrahydrofuran (2.0 mL) was treated with hydrazine monohydrate (0.053mL, 1.093 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.163 mL, 1.093mmol). The solution was heated to 80° C. for 3 h in a Biotage Initiatormicrowave synthesizer. Following cooling, the reaction mixture wastreated with water and extracted twice with EtOAc. The organic layer wasdried over MgSO₄, filtered, concentrated in vacuo, and triturated withCH₂Cl₂ to give the title compound as a white solid (0.026 g; 53%). ¹HNMR (400 MHz, CD₃OD) δ ppm 7.80 (d, J=2.3 Hz, 1 H) 7.67 (dd, J=8.6, 2.3Hz, 1 H) 7.55-7.63 (m, 4 H) 7.36-7.48 (m, 4 H) 7.32 (t, J=7.3 Hz, 1 H)7.10 (d, J=8.8 Hz, 1 H) 4.90 (s, 2 H) 4.73 (qq, J=6.1 Hz, 1 H) 1.35 (d,J=6.1 Hz, 6 H). MS(ES+) m/e 453 [M+H]⁺.

2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({3-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

a) 3-(benzyloxy)benzyl methanesulfonate

Following the procedure of Example 104a), except substituting3-(benzyloxy)benzyl alcohol for 3-(methoxy)-4-(benzyloxy)benzyl alcohol,the title compound was obtained as a colorless oil. MS(ES+) m/e 293[M+H]⁺.

b)5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-({3-[(phenylmethyl)oxy]phenyl}methyl)-1,3,4-oxadiazol-2(3H)-one

Following the procedure of Example 101d), except substituting thecompound from Example 108a) for 4-(bromomethyl)biphenyl, the titlecompound was obtained as a viscous colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.84 (d, J=2.3 Hz, 1 H) 7.64 (dd, J=8.7, 2.1 Hz, 1H) 7.41-7.45 (m, 2 H) 7.37 (tt, J=7.4, 1.6 Hz, 2 H) 7.32 (dd, J=7.1, 1.5Hz, 1 H) 7.28 (d, J=7.8 Hz, 1 H) 6.98-7.02 (m, 2 H) 6.96 (d, J=8.9 Hz, 1H) 6.95 (ddd, J=8.3, 2.5, 0.8 Hz, 1 H) 5.07 (s, 2 H) 4.89 (s, 2 H) 4.65(qq, J=6.1 Hz, 1 H) 1.41 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 451 [M+H]⁺.

c)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-({3-[(phenylmethyl)oxy]phenyl}methyl)hydrazinecarboxamide

A solution of the compound from Example 108b) (0.050 g, 0.111 mmol) intetrahydrofuran (2.0 mL) was treated with methylamine (0.554 mL, 2.0 Msolution in tetrahydrofuran, 1.109 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.331 mL, 2.218 mmol). The solutionwas heated to 100° C. for 4 h in a Biotage Initiator microwavesynthesizer. Following cooling, the reaction mixture was treated withwater and extracted thrice with EtOAc. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (30-80% EtOAc/hexanes) gave the title compound asa white solid (0.045 g; 84%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61(d, J=2.0 Hz, 1 H) 7.50 (dd, J=8.6, 2.3 Hz, 1 H) 7.36-7.43 (m, 4 H) 7.35(d, J=7.6 Hz, 1 H) 7.30 (tt, J=6.9, 1.6 Hz, 1 H) 7.23 (dd, J=8.8, 7.8Hz, 1 H) 6.91 (d, J=6.3 Hz, 2 H) 6.89 (d, J=8.8 Hz, 1 H) 6.85 (d, J=7.6Hz, 1 H) 5.19 (q, J=4.8 Hz, 1 H) 5.01 (s, 2 H) 4.82 (s, 2 H) 4.63 (qq,J=6.1 Hz, 1 H) 2.82 (d, J=4.8 Hz, 3 H) 1.39 (d, J=6.1 Hz, 6 H). MS(ES+)m/e 482 [M+H]⁺.

2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-[(2-phenyl-1H-benzimidazol-5-yl)methyl]hydrazinecarboxamide

a) methyl 2-phenyl-1H-benzimidazole-5-carboxylate

An aqueous solution of NaHSO₃ (21.0 mL, 40% in water) was treatedbenzaldehyde (2.00 mL, 20.0 mmol) and stirred at ambient temperature for1 h. A solution of methyl 3,4-diaminobenzoate (3.32 g, 20.0 mmol) inethanol (15.0 mL) was added and the solution was heated to reflux for 6h. Upon cooling, the solution was poured into water and the resultantprecipitate was collected by filtration, washed with water, and dried invacuo to provide the title compound as a grey solid (4.90 g; 97%). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 10.85 (br. s., 1 H) 8.35 (s, 1 H) 8.11(d, J=2.0 Hz, 1 H) 8.10 (d, J=4.0 Hz, 1 H) 7.97 (dd, J=8.6, 1.5 Hz, 1 H)7.63 (d, J=5.8 Hz, 1 H) 7.46 (d, J=2.3 Hz, 2 H) 7.45 (dd, J=5.5, 4.0 Hz,1 H) 3.94 (s, 3 H). MS(ES+) m/e 253 [M+H]⁺.

b) (2-phenyl-1H-benzimidazol-5-yl)methanol

A solution of the compound from Example 109a) (1.00 g, 4.00 mmol) intetrahydrofuran (25.0 mL) was treated with lithium aluminum hydride(8.00 mL, 1.0 M solution in diethyl ether, 8.00 mmol) at 0° C. Thesolution was allowed to warm slowly to ambient temperature whilestirring for 72 h. The reaction was quenched with saturated aqueousNH₄Cl at 0° C. and extracted thrice with EtOAc. The organic layer wasdried over MgSO₄, filtered, and concentrated in vacuo. Purification viaflash column chromatography (0-10% MeOH/EtOAc) gave the title compoundas a beige solid (0.818 g; 92%). ¹H NMR (400 MHz, MeOH) δ ppm 8.08 (dd,J=8.1, 1.5 Hz, 2 H) 7.62 (s, 1 H) 7.57 (d, J=8.3 Hz, 1 H) 7.47-7.56 (m,3 H) 7.27 (dd, J=8.3, 1.3 Hz, 1 H) 4.73 (s, 2 H). MS(ES+) m/e 225[M+H]⁺.

c) 5-(bromomethyl)-2-phenyl-1H-benzimidazole

A slurry of the compound from Example 109b) (0.218 g, 0.972 mmol) andtriphenylphosphine (0.382 g, 1.46 mmol) in tetrahydrofuran (10.0 mL) wastreated with carbon tetrabromide (0.484 g, 1.46 mmol). After stirring 2h at ambient temperature, the reaction mixture was diluted with brineand extracted thrice with EtOAc. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. Purification via flash columnchromatography (10-70% EtOAc/hexanes) gave the title compound as a whitesolid (0.189 g; 68%). MS(ES+) m/e 287/289 [M+H]⁺.

d)5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-[(2-phenyl-1H-benzimidazol-5-yl)methyl]-1,3,4-oxadiazol-2(3H)-one

Following the procedure of Example 101d), except substituting thecompound from Example 109c) for 4-(bromomethyl)biphenyl, the titlecompound was obtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 11.04 (br. s., 1 H) 8.02-8.12 (m, 2 H) 7.78 (d, J=2.0 Hz, 1 H) 7.63(s, 1 H) 7.57 (dd, J=8.7, 2.1 Hz, 2 H) 7.35-7.46 (m, 3 H) 7.27 (dd,J=8.2, 1.3 Hz, 1 H) 6.91 (d, J=8.8 Hz, 1 H) 5.01 (s, 2 H) 4.61 (qq,J=6.1, 5.9 Hz, 1 H) 1.38 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 461 [M+H]⁺.

e)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-[(2-phenyl-1H-benzimidazol-5-yl)methyl]hydrazinecarboxamide

Following the procedure of Example 104c), except substituting thecompound from Example 109d) for the compound from Example 104b), thetitle compound was obtained as a white solid. ¹H NMR (400 MHz, MeOD) δppm 8.06 (dd, J=8.0, 1.6 Hz, 2 H) 7.77 (d, J=2.3 Hz, 1 H) 7.63 (dd,J=8.6, 2.3 Hz, 1 H) 7.56 (d, J=8.1 Hz, 1 H) 7.52 (d, J=7.8 Hz, 2 H)7.45-7.57 (m, 2 H) 7.27 (dd, J=8.1, 1.3 Hz, 1 H) 7.05 (d, J=8.8 Hz, 1 H)6.79 (q, J=4.0 Hz, 1 H) 4.69 (qq, J=6.0 Hz, 1 H) 2.77 (d, J=4.3 Hz, 3 H)2.69 (s, 2 H) 1.32 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 492 [M+H]⁺.

1-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methylhydrazinecarboxamide

a) methyl 4-(1H-benzimidazol-2-yl)benzoate

An aqueous solution of NaHSO₃ (20.0 mL, 40% in water) was treated with asolution of methyl 4-formylbenzoate (2.20 g, 13.4 mmol) in ethanol (15.0mL) and stirred at ambient temperature for 1 h. 1,2-benzenediamine (1.45g, 13.4 mmol) was added and the solution was heated to reflux overnight.Upon cooling, the solution was poured into ice water and the resultantprecipitate was collected by filtration, washed with water, and dried invacuo to provide the title compound as a grey solid (3.40 g; 100%). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.19 (d, J=7.8 Hz, 2 H) 8.15 (d, J=7.8Hz, 2 H) 7.70 (s, 2 H) 7.34 (dd, J=6.1, 3.3 Hz, 2 H) 3.98 (s, 3 H).MS(ES+) m/e 253 [M+H]⁺.

b) [4-(1H-benzimidazol-2-yl)phenyl]methanol

A solution of the compound from Example 110a) (0.500 g, 1.98 mmol) intetrahydrofuran (10.0 mL) was treated with lithium aluminum hydride(3.96 mL, 1.0 M solution in diethyl ether, 3.96 mmol). After stirring 1h at ambient temperature, the reaction mixture was poured onto ice,treated with saturated aqueous NH₄Cl, diluted with brine and extractedthrice with EtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo to give the title compound as a white solid (0.442g; 99%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.9 (s, 1 H) 8.14 (d, J=7.8Hz, 2 H) 7.59 (s, 2 H) 7.49 (d, J=7.8 Hz, 2 H) 7.20 (d, J=2.0 Hz, 2 H)5.33 (t, J=5.3 Hz, 1 H) 4.59 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 225 [M+H]⁺.

c) 2-[4-(bromomethyl)phenyl]-1H-benzimidazole

A slurry of the compound from Example 110b) (0.650 g, 2.90 mmol) andtriphenylphosphine (1.14 g, 4.35 mmol) in tetrahydrofuran (30.0 mL) wastreated with carbon tetrabromide (1.44 g, 4.35 mmol). After stirringovernight at ambient temperature, the reaction mixture was diluted withwater and extracted with EtOAc. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. Purification via flash columnchromatography (0-100% EtOAc/hexanes) gave the title compound as a greysolid (0.120 g; 14%). MS(ES+) m/e 287/289 [M+H]⁺.

d)3-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-oxadiazol-2(3H)-one

A solution of the compound from Example 101c) (0.319 g, 1.25 mmol) inN,N-dimethylformamide (3.0 mL) was treated with the compound fromExample 101c) (0.120 g, 0.420 mmol) and K₂CO₃ (0.173 g, 1.25 mmol). Thereaction mixture was heated to 80° C. for 30 min. in a Biotage Initiatormicrowave synthesizer. Following cooling, the reaction mixture wastreated with water and extracted with CH₂Cl₂. The organic layer wasdried over MgSO₄, filtered, and concentrated in vacuo. Purification viaflash column chromatography (0-100% EtOAc/hexanes) gave the titlecompound as a yellow solid (0.373 g; 65%). MS(ES+) m/e 461 [M+H]⁺.

e)2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methyl-1-[(2-phenyl-1H-benzimidazol-5-yl)methyl]hydrazinecarboxamide

Following the procedure of Example 104c), except substituting thecompound from Example 110d) for the compound from Example 104b), thetitle compound was obtained as a yellow solid. 1H NMR (400 MHz, MeOH) δppm 8.07 (d, J=8.3 Hz, 2 H) 7.87 (d, J=2.0 Hz, 1 H) 7.72 (dd, J=8.6, 2.3Hz, 1 H) 7.61 (dd, J=6.1, 3.3 Hz, 2 H) 7.54 (d, J=8.3 Hz, 2 H) 7.28 (dd,J=6.1, 3.0 Hz, 2 H) 7.12 (d, J=8.8 Hz, 1 H) 6.86-6.95 (m, 1 H)) 4.69(qq, J=6.1 Hz, 1 H) 2.79 (s, 1 H) 2.78 (s, 2 H) 1.36 (d, J=6.1 Hz, 6 H).MS(ES+) m/e 492 [M+H]⁺.

1-[(4-bromophenyl)methyl]-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methylhydrazinecarboxamide

a)3-[(4-bromophenyl)methyl]-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-oxadiazol-2(3H)-one

Following the procedure of Example 101d), except substituting4-bromobenzyl bromide for 4-(bromomethyl)biphenyl, the title compoundwas obtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) □ ppm 7.82(d, J=2.0 Hz, 1 H) 7.62 (dd, J=8.6, 2.0 Hz, 1 H) 7.49 (d, J=8.3 Hz, 2 H)7.28 (d, J=8.3 Hz, 2 H) 6.95 (d, J=8.6 Hz, 1 H) 4.87 (s, 2 H) 4.64 (qq,J=6.1 Hz, 1 H) 1.40 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 423/425 [M+H]⁺.

b)1-[(4-bromophenyl)methyl]-2-({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)-N-methylhydrazinecarboxamide

Following the procedure of Example 104c), except substituting thecompound from Example 111a) for the compound from Example 104b), thetitle compound was obtained as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.71 (s, 1 H) 7.68 (s, 1 H) 7.55 (d, J=8.3 Hz, 1 H)7.43 (d, J=7.8 Hz, 2 H) 7.17 (d, J=7.6 Hz, 2 H) 6.92 (d, J=8.6 Hz, 1 H)5.23 (q, J=3.0 Hz, 1 H) 4.77 (s, 2 H) 4.65 (qq, J=6.1 Hz, 1 H) 2.79 (d,J=3.0 Hz, 3 H) 1.40 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 454/456 [M+H]⁺.

3-chloro-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]-N′-({4-[(phenylmethyl)oxy]phenyl}methyl)benzohydrazide

a)3-chloro-4-[(1-methylethyl)oxy]-N′-({4-[(phenylmethyl)oxy]phenyl}methyl)benzohydrazide

A solution of the compound from Example 101b) (0.228 g, 1.00 mmol) inmethanol (10.0 mL) was treated with 4-(benzyloxy)benzaldehyde (0.212 g,1.00 mmol) and heated to reflux for 2 h. Following cooling, sodiumcyanoborohydride (0.063 g, 1.00 mmol) and p-toluenesulfonic acidmonohydrate (0.190 g, 1.00 mmol) were added and the solution stirred 2 hat ambient temperature. The reaction was quenched with 1N aqueous NaOH,diluted with brine, and extracted thrice with EtOAc. The organic layerwas dried over MgSO₄, filtered, and concentrated in vacuo. Purificationvia flash column chromatography (10-50% EtOAc/hexanes) gave the titlecompound as a white solid (0.305 g; 72%). ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.75 (d, J=2.3 Hz, 1 H) 7.57 (dd, J=8.6, 2.3 Hz, 1 H) 7.41-7.45(m, 2 H) 7.38 (t, J=7.3 Hz, 2 H) 7.31-7.35 (m, 1 H) 7.30 (d, J=8.3 Hz, 2H) 6.95 (d, J=8.6 Hz, 2 H) 6.91 (d, J=8.6 Hz, 1 H) 5.05 (s, 2 H) 4.62(qq, J=6.0 Hz, 1 H) 4.00 (s, 2 H) 1.39 (d, J=6.1 Hz, 6 H). MS(ES+) m/e425 [M+H]⁺.

b)3-chloro-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]-N′-({4-[(phenylmethyl)oxy]phenyl}methyl)benzohydrazide

A solution of the compound from Example 112a) (0.070 g, 0.165 mmol) inethanol (5.0 mL) was treated with 2-bromoethanol (0.175 mL, 2.47 mmol)and K₂CO₃ (0.068 g, 0.494 mmol). The reaction mixture was heated to 100°C. for 3 h in a Biotage Initiator microwave synthesizer. Followingcooling, the reaction mixture was concentrated in vacuo, diluted withwater, and extracted thrice with EtOAc. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (50-80% EtOAc/hexanes) gave the title compound asa glassy solid (0.066 g; 85%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.33 (s,1 H) 7.74 (d, J=2.3 Hz, 1 H) 7.64 (dd, J=8.6, 2.3 Hz, 1 H) 7.42 (d,J=6.7 Hz, 2 H) 7.36 (t, J=7.3 Hz, 2 H) 7.30-7.33 (m, 1 H) 7.29 (d, J=8.8Hz, 2 H) 7.21 (d, J=8.8 Hz, 1 H) 6.92 (d, J=8.6 Hz, 2 H) 5.04 (s, 2 H)4.75 (qq, J=6.0, 5.8 Hz, 1 H) 4.45 (t, J=5.8 Hz, 1 H) 4.00 (s, 2 H) 3.44(q, J=5.5 Hz, 2 H) 2.91 (t, J=5.8 Hz, 2 H) 1.29 (d, J=6.1 Hz, 6 H).MS(ES+) m/e 469 [M+H]⁺.

3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

a) 4-(4-bromophenyl)-2-(1,1-dimethylethyl)-1H-imidazole

A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) inN,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidinehydrochloride (2.05 g, 15.0 mmol) and K₂CO₃ (4.15 g, 30.0 mmol) andheated to 50° C. for 4 h. Following cooling, the reaction was quenchedwith water, diluted with brine, and extracted thrice with EtOAc. Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuo.Purification via flash column chromatography (10-40% EtOAc/hexanes) gavethe title compound as a light yellow solid (3.38 g; 81%). ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2 H) 7.46 (d, J=8.6 Hz, 2 H)7.18 (s, 1 H) 1.42 (s, 9 H). MS(ES+) m/e 279/281 [M+H]⁺.

b) 4-[2-(1,1-dimethylethyl)-1H-imidazol-4-yl]benzaldehyde

A solution of the compound from Example 113a) (0.558 g, 2.00 mmol) intetrahydrofuran (20.0 mL) was treated with sodium hydride (0.096 g, 60%dispersion in mineral oil, 2.40 mmol). After stirring 15 min. at ambienttemperature, the reaction mixture was cooled to −78° C. and n-BuLi (1.50mL, 1.6 M solution in hexanes, 2.40 mmol) was added. After stirring 1 hat −78° C., N,N-dimethylformamide (0.372 mL, 4.80 mmol) was added andthe cooling bath removed, allowing the reaction to warm slowly toambient temperature over 1 h. The reaction was quenched with water,diluted with brine, and extracted twice with EtOAc. The organic layerwas dried over MgSO₄, filtered, and concentrated in vacuo. Purificationvia flash column chromatography (10-35% EtOAc/hexanes) gave the titlecompound as a light yellow solid (0.310 g; 68%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.95 (s, 1 H) 7.89 (d, J=8.2 Hz, 2 H) 7.85 (d, J=8.2Hz, 2 H) 7.36 (s, 1 H) 1.42 (s, 9 H). MS(ES+) m/e 229 [M+H]⁺.

c)3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 112a), except substituting thecompound from Example 113b) for 4-(benzyloxy)benzaldehyde, the titlecompound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.02 (s, 1 H) 7.86 (d, J=2.0 Hz, 1 H) 7.77-7.83 (m, 1 H) 7.75 (d, J=8.9Hz, 1 H) 7.74 (d, J=8.3 Hz, 2 H) 7.46 (d, J=7.8 Hz, 2 H) 7.23 (d, J=8.8Hz, 1 H) 5.52 (s, 1 H) 4.76 (qq, J=6.1 Hz, 1 H) 4.00 (s, 2 H) 1.41 (s, 9H) 1.30 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 441 [M+H]⁺.

d)3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 113c) (0.114 g, 0.259 mmol) inmethanol (5.0 mL) was treated with (t-butyldimethylsilyloxy)acetaldehyde(0.049 mL, 0.259 mmol) and heated to reflux for 2 h. Following cooling,sodium cyanoborohydride (0.049 g, 0.780 mmol) and p-toluenesulfonic acidmonohydrate (0.148 g, 0.778 mmol) were added and the solution stirred 2h at ambient temperature. Additional p-toluenesulfonic acid monohydrate(0.344 g, 1.808 mmol) was added and the solution stirred overnight atambient temperature. The reaction was quenched with 6N aqueous NaOH,diluted with brine, and extracted thrice with EtOAc. The organic layerwas dried over MgSO₄, filtered, and concentrated in vacuo. Purificationvia flash column chromatography (0-10% MeOH/EtOAc) gave the titlecompound as a white solid (0.108 g; 86%). ¹H NMR (400 MHz, DMSO-d₆) δppm 9.35 (s, 1 H) 7.74 (d, J=2.3 Hz, 1 H) 7.65 (d, J=8.1 Hz, 2 H) 7.63(dd, J=8.8, 2.3 Hz, 1 H) 7.50 (s, 1 H) 7.38 (d, J=7.8 Hz, 2 H) 7.19 (d,J=8.8 Hz, 1 H) 4.74 (qq, J=6.1 Hz, 1 H) 4.47 (t, J=6.1 Hz, 1 H) 4.08 (s,2 H) 3.47 (q, J=5.7 Hz, 2 H) 3.39 (s, 1 H) 2.95 (t, J=5.7 Hz, 2 H) 1.33(s, 9 H) 1.28 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 485 [M+H]⁺.

3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

a) 4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]benzaldehyde

A solution of the compound from Example 113a) (0.890 g, 3.19 mmol) intetrahydrofuran (20.0 mL) was treated with sodium hydride (0.153 g, 60%dispersion in mineral oil, 3.83 mmol). After stirring 15 min. at ambienttemperature, methyl trifluoromethanesulfonate 0.361 mL, 3.19 mmol) wasadded and the solution stirred 30 min. at ambient temperature. Thereaction mixture was then cooled to −78° C. and n-BuLi (2.39 mL, 1.6 Msolution in hexanes, 3.83 mmol) was added. After stirring 30 min. at−78° C., N,N-dimethylformamide (0.592 mL, 7.65 mmol) was added and thecooling bath was allowed to warm slowly to 0° C. The reaction wasquenched with water, diluted with brine, and extracted twice with EtOAc.The organic layer was dried over MgSO₄, filtered, and concentrated invacuo. Purification via flash column chromatography (10-25%EtOAc/hexanes) gave the title compound as a light yellow solid (0.494 g;64%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.95 (s, 1 H) 7.90 (d, J=8.3Hz, 2 H) 7.84 (d, J=8.3 Hz, 2 H) 7.19 (s, 1 H) 3.80 (s, 3 H) 1.48 (s, 9H). MS(ES+) m/e 243 [M+H]⁺.

b)3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 112a), except substituting thecompound from Example 114a) for 4-(benzyloxy)benzaldehyde, the titlecompound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.03 (s, 1 H) 7.86 (d, J=2.0 Hz, 1 H) 7.75 (dd, J=8.7, 2.1 Hz, 1 H)7.63 (d, J=8.1 Hz, 2 H) 7.46 (s, 1 H) 7.32 (d, J=7.6 Hz, 2 H) 7.23 (d,J=9.1 Hz, 1 H) 5.38 (s, 1 H) 4.76 (qq, J=6.1 Hz, 1 H) 3.93 (s, 2 H) 3.76(s, 3 H) 1.40 (s, 9 H) 1.30 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 455 [M+H]⁺.

c)3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 114b) (0.098 g, 0.215 mmol) inmethanol (10.0 mL) was treated with(t-butyldimethylsilyloxy)acetaldehyde (0.041 mL, 0.215 mmol) and heatedto reflux for 1 h. Following cooling, sodium cyanoborohydride (0.014 g,0.215 mmol) and p-toluenesulfonic acid monohydrate (0.082 g, 0.431 mmol)were added and the solution stirred 2 h at ambient temperature.Additional sodium cyanoborohydride (0.056 g, 0.891 mmol) andp-toluenesulfonic acid monohydrate (0.082 g, 0.431 mmol) were added andthe solution stirred overnight at ambient temperature. Additionalp-toluenesulfonic acid monohydrate (0.205 g, 1.078 mmol) was added andthe solution stirred 24 h at ambient temperature. The reaction wasquenched with 6N aqueous NaOH, diluted with brine, and extracted thricewith EtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. Purification via flash column chromatography(0-10% MeOH/EtOAc) gave the title compound as a white solid (0.056 g;52%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.33 (s, 1 H) 7.74 (d, J=2.0 Hz, 1H) 7.62 (dd, J=8.6, 2.3 Hz, 1 H) 7.58 (d, J=8.1 Hz, 2 H) 7.40 (s, 1 H)7.32 (d, J=8.1 Hz, 2 H) 7.19 (d, J=8.8 Hz, 1 H) 4.74 (qq, J=6.1 Hz, 1 H)4.46 (t, J=6.1 Hz, 1 H) 4.05 (s, 2 H) 3.73 (s, 3 H) 3.46 (q, J=5.7 Hz, 2H) 2.93 (t, J=5.7 Hz, 2 H) 1.37 (s, 9 H) 1.28 (d, J=6.1 Hz, 6 H).MS(ES+) m/e 499 [M+H]⁺.

3-chloro-N′-[(4-{[(4-fluorophenyl)methyl]oxy}phenyl)methyl]-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 101b) (0.100 g, 0.437 mmol) inmethanol (10.0 mL) was treated with 4-(4-fluorobenzyloxy)benzaldehyde(0.101 g, 0.437 mmol) and heated to reflux for 1 h. Following cooling,sodium cyanoborohydride (0.082 g, 1.31 mmol) and p-toluenesulfonic acidmonohydrate (0.249 g, 1.31 mmol) were added and the solution was stirred1 h at ambient temperature. (t-Butyldimethylsilyloxy)acetaldehyde (0.083mL, 0.437 mmol) was added and the solution was stirred 1 h at ambienttemperature. Additional p-toluenesulfonic acid monohydrate (0.083 g,0.437 mmol) was added and the solution was stirred overnight at ambienttemperature. The reaction was quenched with 6N aqueous NaOH, dilutedwith brine, and extracted thrice with EtOAc. The organic layer was driedover MgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (40-80% EtOAc/hexanes) gave the title compound asa white solid (0.166 g; 78%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H) 7.74 (d, J=2.0 Hz, 1 H) 7.64 (dd, J=8.6, 2.3 Hz, 1 H) 7.47 (d, J=8.6Hz, 1 H) 7.46 (d, J=8.6 Hz, 1 H) 7.29 (d, J=8.6 Hz, 2 H) 7.21 (d, J=9.0Hz, 1 H) 7.14-7.20 (m, 2 H) 6.92 (d, J=8.8 Hz, 2 H) 5.02 (s, 2 H) 4.75(qq, J=6.1 Hz, 1 H) 4.44 (t, J=5.6 Hz, 1 H) 4.00 (s, 2 H) 3.44 (q, J=5.8Hz, 2 H) 2.90 (t, J=5.8 Hz, 2 H) 1.29 (d, J=5.8 Hz, 6 H). MS(ES+) m/e487 [M+H]⁺.

3-cyano-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

a) 3-cyano-4-[(1-methylethyl)oxy]benzohydrazide

A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.300 g, 1.46mmol) in tetrahydrofuran (10.0 mL) was treated with1,1′-carbonyldiimidazole (0.261 g, 1.61 mmol). After stirring 2 h atambient temperature, hydrazine monohydrate (0.213 mL, 4.39 mmol) wasadded. After stirring an additional 2 h at ambient temperature, thereaction mixture was concentrated in vacuo. Purification via flashcolumn chromatography (0-5% MeOH/EtOAc) gave the title compound as awhite solid (0.304 g; 95%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51(br. s., 1 H) 8.06 (d, J=2.3 Hz, 1 H) 8.02 (dd, J=8.8, 2.3 Hz, 1 H) 7.00(d, J=8.8 Hz, 1 H) 5.15 (br. s., 2 H) 4.71 (qq, J=6.1 Hz, 1 H) 1.40 (d,J=6.1 Hz, 6 H). MS(ES+) m/e 220 [M+H]⁺.

b)3-cyano-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

A solution of the compound from Example 116a) (0.036 g, 0.165 mmol) inmethanol (5.0 mL) was treated with the compound from Example 114a)(0.040 g, 0.165 mmol) and heated to reflux for 1 h. Following cooling,sodium cyanoborohydride (0.031 g, 0.495 mmol) and p-toluenesulfonic acidmonohydrate (0.095 g, 0.499 mmol) were added and the solution wasstirred 30 min. at ambient temperature.(t-Butyldimethylsilyloxy)acetaldehyde (0.031 mL, 0.165 mmol) was addedand the solution was stirred 30 min. ambient temperature. Additionalp-toluenesulfonic acid monohydrate (0.031 g, 0.165 mmol) was added andthe solution was stirred 30 min. at ambient temperature. The reactionwas quenched with 6N aqueous NaOH, diluted with brine, and extractedthrice with EtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. Purification via flash column chromatography(40-100% EtOAc/hexanes) gave the title compound as a white solid (0.053g; 66%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.41 (s, 1 H) 8.01 (d, J=2.3Hz, 1 H) 7.94 (dd, J=8.8, 2.3 Hz, 1 H) 7.58 (d, J=8.3 Hz, 2 H) 7.41 (s,1 H) 7.32 (d, J=8.6 Hz, 3 H) 4.84 (qq, J=6.1 Hz, 1 H) 4.44 (t, J=6.1 Hz,1 H) 4.05 (s, 2 H) 3.73 (s, 3 H) 3.47 (q, J=5.8 Hz, 2 H) 2.94 (t, J=5.8Hz, 2 H) 1.37 (s, 9 H) 1.30 (d, J=5.8 Hz, 6 H). MS(ES+) m/e 490 [M+H]⁺.

N′-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}-3-chloro-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

a) 4-(1H-benzimidazol-2-yl)benzaldehyde

A solution of the compound from Example 110b) (0.224 g, 1.00 mmol) inacetone (30.0 mL) was treated with activated manganese dioxide (0.869 g,10.0 mmol) and stirred overnight at ambient temperature. The reactionmixture was filtered through celite, washed through with acetone, andconcentrated in vacuo to give the title compound as a light yellow solid(0.218 g; 98%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br. s., 1 H)10.08 (s, 1 H) 8.39 (d, J=8.3 Hz, 2 H) 8.08 (d, J=8.3 Hz, 2 H) 7.56-7.81(m, 2 H) 7.25 (dd, J=6.1, 3.0 Hz, 2 H). MS(ES+) m/e 223 [M+H]⁺.

b)N′-{[4-(1H-benzimidazol-2-yl)phenyl]methyl}-3-chloro-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting thecompound from Example 101b) for the compound from Example 116a) and thecompound from Example 117a) for the compound from Example 114a), thetitle compound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 12.8 (s, 1 H) 9.44 (s, 1 H) 8.08 (d, J=8.3 Hz, 2 H) 7.75 (d, J=2.3Hz, 1 H) 7.64 (dd, J=8.7, 2.1 Hz, 1 H) 7.56 (d, J=8.1 Hz, 2 H) 7.41-7.68(m, 2 H) 7.20 (d, J=8.8 Hz, 2 H) 7.15-7.20 (m, 1 H) 4.73 (qq, J=6.1 Hz,1 H) 4.50 (t, J=6.1 Hz, 1 H) 4.17 (s, 2 H) 3.49 (q, J=5.6 Hz, 2 H) 2.99(t, J=5.7 Hz, 2 H) 1.27 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 479 [M+H]⁺.

3-chloro-N′-({4-[(cyclohexylmethyl)oxy]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

a) 4-[(cyclohexylmethyl)oxy]benzaldehyde

A solution of 4-hydroxybenzaldehyde (0.244 g, 2.00 mmol) in CH₃CN (4.0mL) was treated with bromomethylcyclohexane (0.279 g, 2.00 mmol) andK₂CO₃ (0.332 g, 2.40 mmol). The reaction mixture was heated to 100° C.for 1 h in a Biotage Initiator microwave synthesizer. Additionalbromomethylcyclohexane (0.279 g, 2.00 mmol) and K₂CO₃ (0.332 g, 2.40mmol) were added and the reaction mixture was again heated to 100° C.for 1 h in a Biotage Initiator microwave synthesizer. Additionalbromomethylcyclohexane (0.279 g, 2.00 mmol) and K₂CO₃ (0.332 g, 2.40mmol) were added and the reaction mixture was again heated to 100° C.for 1 h in a Biotage Initiator microwave synthesizer. Following cooling,the reaction mixture was filtered and concentrated in vacuo.Purification via flash column chromatography (10% EtOAc/hexanes) gavethe title compound as a white solid (0.360 g; 82%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.86 (s, 1 H) 7.85 (d, J=8.8 Hz, 2 H) 7.11 (d, J=8.8 Hz,2 H) 3.89 (d, J=6.3 Hz, 2 H) 1.80 (d, J=12.6 Hz, 2 H) 1.61-1.79 (m, 4 H)1.13-1.32 (m, 3 H) 1.07 (dd, J=12.6, 2.6 Hz, 1 H) 1.01 (dd, J=11.9, 2.5Hz, 1 H). MS(ES+) m/e 219 [M+H]⁺.

b)3-chloro-N′-({4-[(cyclohexylmethyl)oxy]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting thecompound from Example 101b) for the compound from Example 116a) and thecompound from Example 118a) for the compound from Example 114a), thetitle compound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 9.31 (s, 1 H) 7.73 (d, J=2.0 Hz, 1 H) 7.64 (dd, J=8.6, 2.3 Hz, 1H) 7.25 (d, J=8.6 Hz, 2 H) 7.20 (d, J=8.8 Hz, 1 H) 6.81 (d, J=8.6 Hz, 2H) 4.75 (qq, J=6.1 Hz, 1 H) 4.44 (t, J=5.9 Hz, 1 H) 3.98 (s, 2 H) 3.70(d, J=6.3 Hz, 2 H) 3.43 (q, J=6.0 Hz, 2 H) 2.90 (t, J=5.8 Hz, 2 H) 1.76(d, J=12.4 Hz, 2 H) 1.57-1.72 (m, 4 H) 1.29 (d, J=6.1 Hz, 6 H) 1.11-1.25(m, 3 H) 1.02 (dd, J=12.1, 2.6 Hz, 1 H) 0.96 (dd, J=11.4, 2.5 Hz, 1 H).MS(ES+) m/e 475 [M+H]⁺.

3-cyano-N′-({4-[(cyclohexylmethyl)oxy]phenyl}methyl)-N′-(2-hydroxyethyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting thecompound from Example 118a) for the compound from Example 114a), thetitle compound was obtained as a glassy solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 9.37 (s, 1 H) 7.99 (d, J=2.3 Hz, 1 H) 7.95 (dd, J=8.8, 2.3 Hz, 1H) 7.33 (d, J=9.1 Hz, 1 H) 7.25 (d, J=8.8 Hz, 2 H) 6.82 (d, J=8.8 Hz, 2H) 4.86 (qq, J=6.1 Hz, 1 H) 4.41 (t, J=6.1 Hz, 1 H) 3.98 (s, 2 H) 3.71(d, J=6.6 Hz, 2 H) 3.44 (q, J=6.0 Hz, 2 H) 2.90 (t, J=5.8 Hz, 2 H) 1.77(d, J=12.4 Hz, 2 H) 1.58-1.72 (m, 4 H) 1.31 (d, J=6.1 Hz, 6 H) 1.12-1.28(m, 3 H) 1.03 (dd, J=12.5, 2.0 Hz, 1 H) 0.95-1.00 (m, J=11.1, 2.5 Hz, 1H). MS(ES+) m/e 466 [M+H]⁺.

3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting thecompound from Example 101b) for the compound from Example 116a) and3-(t-butyldimethylsilyloxy)propanal (prepared by the method of Berque,I.; Le Ménez, P.; Razon, P.; Mahuteau, J.; Férezou, J.-P.; Pancrazi, A.;Ardisson, J.; Brion, J.-D., J. Org. Chem., 1999, 64, 373-381) for(t-butyldimethylsilyloxy)acetaldehyde, the title compound was obtainedas a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.24 (s, 1 H)7.76 (d, J=2.3 Hz, 1 H) 7.64 (dd, J=8.6, 2.3 Hz, 1 H) 7.58 (d, J=8.3 Hz,2 H) 7.41 (s, 1 H) 7.30 (d, J=8.3 Hz, 2 H) 7.19 (d, J=9.1 Hz, 1 H) 4.74(qq, J=6.1 Hz, 1 H) 4.45 (t, J=5.2 Hz, 1 H) 3.97 (s, 2 H) 3.73 (s, 3 H)3.48 (q, J=6.1 Hz, 2 H) 2.91 (t, J=6.8 Hz, 2 H) 1.53-1.67 (m, 2 H) 1.37(s, 9 H) 1.28 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 513 [M+H]⁺.

3-cyano-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-(3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting3-(t-butyldimethylsilyloxy)propanal (prepared by the method of Berque,I.; Le Ménez, P.; Razon, P.; Mahuteau, J.; Férezou, J.-P.; Pancrazi, A.;Ardisson, J.; Brion, J.-D., J. Org. Chem., 1999, 64, 373-381) for(t-butyldimethylsilyloxy)acetaldehyde, the title compound was obtainedas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.29 (s, 1 H) 8.03 (d,J=2.3 Hz, 1 H) 7.95 (dd, J=8.8, 2.3 Hz, 1 H) 7.58 (d, J=8.1 Hz, 2 H)7.41 (s, 1 H) 7.31 (d, J=9.1 Hz, 1 H) 7.30 (d, J=8.3 Hz, 2 H) 4.84 (qq,J=6.1 Hz, 1 H) 4.43 (t, J=5.3 Hz, 1 H) 3.97 (s, 2 H) 3.73 (s, 3 H) 3.48(q, J=6.1 Hz, 2 H) 2.91 (t, J=6.8 Hz, 2 H) 1.57-1.64 (m, 2 H) 1.37 (s, 9H) 1.31 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 504 [M+H]⁺.

3-chloro-N′-(2-cyanoethyl)-4-[(1-methylethyl)oxy]-N′-({4-[(phenylmethyl)oxy]phenyl}methyl)benzohydrazide

A solution of pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate(0.100 g, 0.263 mmol) in methanol (5.0 mL) was treated with3-hydrazinopropanenitrile (0.023 mL, 0.289 mmol) and heated to refluxfor 1 h. Following cooling, 4-(benzyloxy)benzaldehyde (0.067 g, 0.315mmol), sodium cyanoborohydride (0.020 g, 0.315 mmol), andp-toluenesulfonic acid monohydrate (0.060 g, 0.315 mmol) were added andthe solution stirred 30 min. at ambient temperature. Additional4-(benzyloxy)benzaldehyde (0.067 g, 0.315 mmol), sodium cyanoborohydride(0.040 g, 0.637 mmol), and p-toluenesulfonic acid monohydrate (0.100 g,0.526 mmol) were added and the solution stirred overnight at ambienttemperature. The reaction was quenched with 6N aqueous NaOH, dilutedwith brine, and extracted thrice with EtOAc. The organic layer was driedover MgSO₄, filtered, and concentrated in vacuo. Purification via flashcolumn chromatography (30-80% EtOAc/hexanes) gave the title compound asa white solid (0.077 g; 61%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61(d, J=2.3 Hz, 1 H) 7.45 (dd, J=8.8, 2.2 Hz, 2 H) 7.42 (s, 1 H) 7.36-7.41(m, 2 H) 7.32 (tt, J=7.0, 1.8 Hz, 1 H) 7.28 (s, 1 H) 7.17 (br. s., 1 H)6.94 (d, J=8.6 Hz, 2 H) 6.88 (d, J=8.6 Hz, 1 H) 5.05 (s, 2 H) 4.61 (qq,J=6.0 Hz, 1 H) 4.22 (s, 2 H) 3.39 (t, J=6.6 Hz, 2 H) 2.60 (t, J=6.6 Hz,2 H) 1.39 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 478 [M+H]⁺.

3-chloro-N′-({4-[2-(1,1-dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}methyl)-N′-[(2-hydroxyphenyl)methyl]-4-[(1-methylethyl)oxy]benzohydrazide

Following the procedure of Example 116b), except substituting thecompound from Example 101b) for the compound from Example 116a) andsalicylaldehyde for (t-butyldimethylsilyloxy)acetaldehyde, the titlecompound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.1 (s, 1 H) 7.76 (d, J=2.3 Hz, 1 H) 7.65 (dd, J=8.7, 2.1 Hz, 1 H) 7.55(d, J=8.3 Hz, 2 H) 7.39 (s, 1 H) 7.13-7.27 (m, 5 H) 6.84 (d, J=8.1 Hz, 1H) 6.79 (dd, J=7.5, 0.9 Hz, 1 H) 6.75 (dd, J=8.7, 0.9 Hz, 1 H) 4.75 (qq,J=5.8 Hz, 1 H) 4.06 (s, 2 H) 3.88 (s, 2 H) 3.72 (s, 3 H) 1.36 (s, 9 H)1.28 (d, J=5.8 Hz, 6 H). MS(ES+) m/e 561 [M+H]⁺.

The procedure of taking compound 6 to compound 8 in Example 100 wasfollowed for making 11.

To a solution of crude 11 (160 mg, 0.97 mmol) in DMF (1 mL) weresuccessively added compound 12 (235 mg, 0.97 mmol), HBTU (396 mg, 1.05mmol) and DIEA (606 μL, 3.48 mmol). The solution was stirred at roomtemperature for 1 hour and purified by RP—HPLC using a mixture ofacetonitrile and H₂O to give 13 (100 mg, 20%). LRMS (M+H⁺) m/z 513.2.

Compound 13 (37 mg, 0.072 mmol), ethyl formate (2 mL) and p-toluenesulfonic acid (4 mg) were mixed in the closed tube and heated to 140° C.for about 8 hours. The solution was concentrated and purified by RP—HPLCusing a mixture of acetonitrile and H₂O to give 14 (10 mg, 27%). LRMS(M+H⁺) m/z 523.2.

Example 125

Inhibition of Cellular Viability in Tumor Cell Lines Treated withMitotic Kinesin Inhibitors

Materials and Solutions:

-   -   Cells: SKOV3, Ovarian Cancer (human).    -   Media: Phenol Red Free RPMI+5% Fetal Bovine Serum+2 mM        L-glutamine.    -   Colorimetric Agent for Determining Cell Viability: Promega MTS        tetrazolium compound.    -   Control Compound for max cell kill: Topotecan, 1 μM.        Procedure: Day 1—Cell Plating:

Adherent SKOV3 cells are washed with 10 mLs of PBS followed by theaddition of 2 mLs of 0.25% trypsin and incubation for 5 minutes at 37°C. The cells are rinsed from the flask using 8 mL of media (phenolred-free RPMI+5% FBS) and transferred to fresh flask. Cell concentrationis determined using a Coulter counter and the appropriate volume ofcells to achieve 1000 cells/100 μL is calculated. 100 μL of media cellsuspension (adjusted to 1000 cells/100 μL) is added to all wells of96-well plates, followed by incubation for 18 to 24. hours at 37° C.,100% humidity, and 5% CO₂, allowing the cells to adhere to the plates.

Procedure: Day 2—Compound Addition:

To one column of the wells of an autoclaved assay block are added aninitial 2.5 μL of test compound(S) at 400× the highest desiredconcentration. 1.25 μL of 400× (400 μM) Topotecan is added to otherwells (ODs from these wells are used to subtract out for backgroundabsorbance of dead cells and vehicle). 500 μL of media without DMSO areadded to the wells containing test compound, and 250 μL to the Topotecanwells. 250 μL of media+0.5% DMSO is added to all remaining wells, intowhich the test compound(S) are serially diluted. By row,compound-containing media is replica plated (in duplicate) from theassay block to the corresponding cell plates. The cell plates areincubated for 72 hours at 37° C., 100% humidity, and 5% CO₂.

Procedure: Day 4—MTS Addition and OD Reading:

The plates are removed from the incubator and 40 μl MTS/PMS is added toeach well. Plates are then incubated for 120 minutes at 37° C., 100%humidity, 5% CO₂, followed by reading the ODs at 490 nm after a 5 secondshaking cycle in a ninety-six well spectrophotometer.

Data Analysis

The normalized % of control (absorbance−background) is calculated and anXLfit is used to generate a dose-response curve from which theconcentration of compound required to inhibit viability by 50% isdetermined. The compounds of the present invention show activity whentested by this method.

Example 126

Application of a Mitotic Kinesin Inhibitor

Human tumor cells Skov-3 (ovarian) were plated in 96-well plates atdensities of 4,000 cells per well, allowed to adhere for 24 hours, andtreated with various concentrations of the test compounds for 24 hours.Cells were fixed in 4% formaldehyde and stained with antitubulinantibodies (subsequently recognized using fluorescently-labeledsecondary antibody) and Hoechst dye (which stains DNA).

Visual inspection revealed that the compounds caused cell cycle arrest.

Example 127

Inhibition of Cellular Proliferation in Tumor Cell Lines Treated withMitotic Kinesin Inhibitors.

Cells were plated in 96-well plates at densities from 1000-2500cells/well of a 96-well plate and allowed to adhere/grow for 24 hours.They were then treated with various concentrations of drug for 48 hours.The time at which compounds are added is considered T₀. Atetrazolium-based assay using the reagent3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) (I.S>U.S. Pat. No. 5,185,450) (see Promega product catalog #G3580,CeIlTiter 96® AQ_(ueous) One Solution Cell Proliferation Assay) was usedto determine the number of viable cells at T₀ and the number of cellsremaining after 48 hours compound exposure. The number of cellsremaining after 48 hours was compared to the number of viable cells atthe time of drug addition, allowing for calculation of growthinhibition.

The growth over 48 hours of cells in control wells that had been treatedwith vehicle only (0.25% DMSO) is considered 100% growth and the growthof cells in wells with compounds is compared to this. Mitotic kinesininhibitors inhibited cell proliferation in human ovarian tumor celllines (SKOV-3).

A Gi₅₀ was calculated by plotting the concentration of compound in μM vsthe percentage of cell growth of cell growth in treated wells. The Gi₅₀calculated for the compounds is the estimated concentration at whichgrowth is inhibited by 50% compared to control, i.e., the concentrationat which:100×[(Treated₄₈ −T ₀)/(Control₄₈ −T ₀)]=50.

All concentrations of compounds are tested in duplicate and controls areaveraged over 12 wells. A very similar 96-well plate layout and Gi₅₀calculation scheme is used by the National Cancer Institute (see Monks,et al., J. NatI. Cancer Inst. 83:757-766 (1991)). However, the method bywhich the National Cancer Institute quantitates cell number does not useMTS, but instead employs alternative methods.

Example 128

Calculation of IC₅₀:

Measurement of a composition's IC₅₀ uses an ATPase assay. The followingsolutions are used: Solution 1 consists of 3 mM phosphoenolpyruvatepotassium salt (Sigma P-7127), 2 mM ATP (Sigma A-3377), 1 mM IDTT (SigmaD-9779), 5 μM paclitaxel (Sigma T-7402), 10 ppm antifoam 289 (SigmaA-8436), 25 mM Pipes/KOH pH 6.8 (Sigma P6757), 2 mM MgCl2 (VWRJT400301), and 1 mM EGTA (Sigma E3889). Solution 2 consists of 1 mM NADH(Sigma N8129), 0.2 mg/ml BSA (Sigma A7906), pyruvate kinase 7U/ml,L-lactate dehydrogenase 10 U/ml (Sigma P0294), 100 nM motor domain of amitotic kinesin, 50 μg/ml microtubules, 1 mM DTT (Sigma D9779), 5 μMpaclitaxel (Sigma T-7402), 10 ppm antifoam 289 (Sigma A-8436), 25 mMPipes/KOH pH 6.8 (Sigma P6757), 2 mM MgCl2 (VWR JT4003-01), and 1 mMEGTA (Sigma E3889). Serial dilutions (8-12 two-fold dilutions) of thecomposition are made in a 96-well microtiter plate (Coming Costar 3695)using Solution 1. Following serial dilution each well has 50 μl ofSolution 1. The reaction is started by adding 50 μl of solution 2 toeach well. This may be done with a multichannel pipettor either manuallyor with automated liquid handling devices. The microtiter plate is thentransferred to a microplate absorbance reader and multiple absorbancereadings at 340 nm are taken for each well in a kinetic mode. Theobserved rate of change, which is proportional to the ATPase rate, isthen plotted as a function of the compound concentration. For a standardIC₅₀ determination the data acquired is fit by the following fourparameter equation using a nonlinear fitting program (e.g., Grafit 4):$y = {\frac{R{ange}}{1 + \left( \frac{x}{{IC}_{50}} \right)^{s}} + {Background}}$where y is the observed rate and x the compound concentration.

Other chemical entities of this class were found to inhibit cellproliferation, although GI₅₀ values varied. GI₅₀ values for the chemicalentities tested ranged from 200 nM to greater than the highestconcentration tested. By this we mean that although most of the chemicalentities that inhibited mitotic kinesin activity biochemically didinhibit cell proliferation, for some, at the highest concentrationtested (generally about 20 μM), cell growth was inhibited less than 50%. Many of the chemical entities have GI₅₀ values less than 10 μM, andseveral have GI₅₀ values less than 1 μM. Anti-proliferative compoundsthat have been successfully applied in the clinic to treatment of cancer(cancer chemotherapeutics) have GI₅₀'s that vary greatly. For example,in A549 cells, paclitaxel GI₅₀ is 4 nM, doxorubicin is 63 nM,5-fluorouracil is 1 μM, and hydroxyurea is 500 μM (data provided byNational Cancer Institute, Developmental Therapeutic Program,http://dtp.nci.nih.gov/). Therefore, compounds that inhibit cellularproliferation at virtually any concentration may be useful.

1. At least one chemical entity chosen from compounds of Formula I

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁ is chosen fromoptionally substituted aryl, optionally substituted heterocycloalkyl,and optionally substituted heteroaryl; X is chosen from —CO and —SO₂—;R₂ is chosen from hydrogen and optionally substituted lower alkyl; W ischosen from —CR₄—, —CH₂CR₄—, and N; R₃ is chosen from —CO—R₇, hydrogen,optionally substituted alkyl, optionally substituted heterocycloalkyl,optionally substituted heteroaryl, cyano, sulfonyl, and optionallysubstituted aryl; R₄ is chosen from hydrogen and optionally substitutedalkyl; R₅ is chosen from hydrogen, hydroxy, optionally substitutedamino, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl;optionally substituted heteroaryl, and optionallysubstituted lower alkyl; R₆ is chosen from hydrogen, optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryloxy, optionally substituted heteraryloxy, optionally substitutedalkoxycarbonyl-, aminocarbonyl-, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl; and R₇ is chosen fromoptionally substituted lower alkyl, optionally substituted aryl,hydroxy, optionally substituted amino, optionally substituted aralkoxy,and optionally substituted alkoxy; provided that if W is N, then R₅ isnot hydroxy or optionally substituted amino, and R₆ is not optionallysubstituted alkoxy, optionally substituted aralkoxy, optionallysubstituted heteroaralkoxy, or optionally substituted amino.
 2. At leastone chemical entity of claim 1 wherein R₁ is optionally substitutedaryl.
 3. At least one chemical entity of claim 2, wherein R₁ isoptionally substituted phenyl.
 4. At least one chemical entity of claim3, wherein R₁ is phenyl substituted with one, two or three groupsindependently selected from optionally substituted heterocycloalkyl,optionally substituted alkyl, sulfonyl, halo, optionally substitutedamino, sulfanyl, optionally substituted alkoxy, optionally substitutedaryloxy, optionally substituted heteroaryloxy; acyl, hydroxy, nitro,cyano, optionally substituted aryl, and optionally substitutedheteroaryl-.
 5. At least one chemical entity of claim 4, wherein R₁ ischosen from 3-halo-4-isopropoxy-phenyl, 3-cyano-4-isopropoxy-phenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-cyano-4-((R)-1,1,1-trifluoropropan-2-yloxy)phenyl,3-halo-4-isopropylamino-phenyl, 3-cyano-4-isopropylamino-phenyl,3-halo-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl, and3-cyano-4-((R)-1,1,1-trifluoropropan-2-ylamino)phenyl.
 6. At least onechemical entity of claim 1 wherein X is —CO—.
 7. At least one chemicalentity of claim 1 wherein the compound of Formula I is chosen fromcompounds of Formula II

wherein R₁₁ is chosen from optionally substituted heterocycloalkyl,optionally substituted heteroaryl, optionally substituted lower alkyl,nitro, cyano, hydrogen, sulfonyl, and halo; R₁₂ is chosen from hydrogen,halo, optionally substituted alkyl, optionally substituted amino,sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, and optionally substituted heteroaryloxy; and R₁₃ ischosen from hydrogen, acyl, optionally substituted alkyl-, optionallysubstituted alkoxy, halo, hydroxy, nitro, cyano, optionally substitutedamino, alkylsulfonyl-, alkylsulfonamido-, carboxyalkyl-, aminocarbonyl-,optionally substituted aryl and optionally substituted heteroaryl-. 8.At least one chemical entity of claim 1 wherein W is —CR₄—.
 9. At leastone chemical entity of claim 1 wherein R₄ is hydrogen.
 10. At least onechemical entity of claim 1 wherein R₅ is chosen from hydrogen, hydroxy,and optionally substituted lower alkyl.
 11. At least one chemical entityof claim 10 wherein R₅ is hydrogen.
 12. At least one chemical entity ofclaim 7 wherein the compound of Formula II is chosen from compounds ofFormula III


13. At least one chemical entity of claim 1 wherein R₃ is chosen from—CO—R₇; hydrogen; optionally substituted lower alkyl; cyano; sulfonyl;optionally substituted aryl; optionally substituted heteroaryl, andoptionally substituted heterocycloalkyl.
 14. At least one chemicalentity of claim 13 wherein R₃ is optionally substituted lower alkyl oroptionally substituted heteroaryl.
 15. At least one chemical entity ofclaim 14 wherein R₃ is chosen from lower alkyl that is optionallysubstituted with a hydroxy or a phosphate or acyl ester thereof, loweralkyl that is optionally substituted with a lower alkoxy, lower alkylthat is optionally substituted with an optionally substituted aminogroup, and lower alkyl that is optionally substituted with CO—R₇ whereR₇ is chosen from hydroxy and optionally substituted amino.
 16. At leastone chemical entity of claim 15 wherein R₃ is chosen from lower alkylthat is optionally substituted with a hydroxy or a phosphate or acylester thereof and lower alkyl that is optionally substituted with anoptionally substituted amino group.
 17. At least one chemical entity ofclaim 12 wherein the compound of Formula III is chosen from compounds ofFormula IV


18. At least one chemical entity of claim 1 wherein R₆ is chosen fromoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, optionally substitutedcycloalkyl, and optionally substituted alkyl.
 19. At least one chemicalentity of claim 18 wherein R₆ is phenyl substituted with one or two ofthe following substituents: optionally substituted heteroaryl,optionally substituted amino, aralkoxy, halo, hydroxymethyl-, hydroxy,cyano, alkoxy, phenyl, phenoxy, methylenedioxy, ethylenedioxy, sulfonyl,aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy,and optionally substituted heterocycloalkyl.
 20. At least one chemicalentity of claim 12 wherein the compound of Formula III is chosen fromcompounds of Formula V

wherein R₁₄ is chosen from optionally substituted heterocycloalkyl andoptionally substituted heteroaryl; and R₁₅ is chosen from hydrogen,halo, hydroxy, and lower alkyl.
 21. At least one chemical entity ofclaim 20, wherein R₁₄ is chosen from7,8-dihydro-imidazo[1,2-c][1,3]oxazin-2-yl,3a,7a-dihydro-1H-benzoimidazol-2-yl, imidazo[2,1-b]oxazol-6-yl,oxazol-4-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl,1H-[1,2,4]triazol-3-yl, 2,3-dihydro-imidazol-4-yl, 1H-imidazol-2-yl,imidazo[1,2-a]pyridin-2-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl,and 1H-imidazol-4-yl, each of which is optionally substituted with one,two, or three groups chosen from optionally substituted lower alkyl,halo, acyl, sulfonyl, cyano, nitro, optionally substituted amino, andoptionally substituted heteroaryl.
 22. At least one chemical entity ofclaim 21, wherein R₁₄ is chosen from 1H-imidazol-2-yl,imidazo[1,2-a]pyridin-2-yl; and 1H-imidazol-4-yl, each of which isoptionally substituted with one or two groups chosen from optionallysubstituted lower alkyl, halo, and acyl.
 23. At least one chemicalentity of claim 20 wherein R₁₅ is hydrogen.
 24. At least one chemicalentity of claim 12 wherein the compound of Formula II is chosen fromcompounds of Formula VI

wherein R₁₆ is chosen from halo, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted alkoxy, and optionallysubstituted amino; and R₁₇ is chosen from hydrogen, lower alkoxy, halo,and lower alkyl.
 25. At least one chemical entity of claim 24 whereinR₁₆ is chosen from optionally substituted phenyl, optionally substitutedheteroaryl, optionally substituted lower alkoxy, and optionallysubstituted amino.
 26. At least one chemical entity of claim 25 whereinR₁₆ is chosen from phenyl, optionally substituted benzyloxy, halo,optionally substituted 1H-imidazol-4-yl, optionally substituted1H-benzo[d]imidazol-2-yl, and optionally substituted cyclohexylmethoxy.27. At least one chemical entity of claim 24 wherein R₁₇ is hydrogen.28. At least one chemical entity of claim 12 wherein the compound ofFormula II is chosen from compounds of Formula VII

wherein R₉ is chosen from optionally substituted alkoxy, optionallysubstituted cycloalkoxy, optionally substituted arylalkoxy, optionallysubstituted amino and optionally substituted lower alkyl.
 29. At leastone chemical entity of claim 25 wherein R₉ is chosen from lower alkylsubstituted with a group chosen from hydroxy and optionally substitutedamino.
 30. At least one chemical entity of claim 26 wherein R₉ is loweralkyl substituted with a group chosen from hydroxy, amino, azetidino,N-methylamino, and N,N-dimethylamino.
 31. At least one chemical entityof claim 7 wherein R₁₁ is chosen from hydrogen, cyano, nitro, and halo.32. At least one chemical entity of claim 28 wherein R₁₁ is chosen fromchloro and cyano.
 33. At least one chemical entity of claim 7 whereinR₁₂ is chosen from optionally substituted lower alkoxy, optionallysubstituted lower alkyl, and optionally substituted amino-.
 34. At leastone chemical entity of claim 30 wherein R₁₂ is chosen lower alkoxy,2,2,2-trifluoro-1-methyl-ethoxy, lower alkylamino or2,2,2-trifluoro-1-methyl-ethylamino.
 35. At least one chemical entity ofclaim 31 wherein R₁₂ is chosen from propoxy,2,2,2-trifluoro-1-methyl-ethoxy, propylamino, or2,2,2-trifluoro-1-methyl-ethylamino.
 36. At least one chemical entity ofclaim 7 wherein R₁₃ is hydrogen.
 37. At least one chemical entity ofclaim 1 wherein R₂ is hydrogen.
 38. At least one chemical entity ofclaim 1 wherein the compound of Formula 1 is chosen from methyl1-(biphenyl-4-ylmethyl)-2-(3-chloro-4-isopropoxybenzoyl)hydrazinecarboxylate;1-(biphenyl-4-ylmethyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;1-(4-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;1-(4-(benzyloxy)-3-methoxybenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;1-(4-benzamidobenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;N-(2-amino-2-oxoethyl)-1-(4-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)hydrazinecarboxamide;1-(3-(benzyloxy)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;2-(3-chloro-4-isopropoxybenzoyl)-N-methyl-1-((2-phenyl-3H-benzo[d]imidazol-5-yl)methyl)hydrazinecarboxamide;1-(4-(1H-benzo[d]imidazol-2-yl)benzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;1-(4-bromobenzyl)-2-(3-chloro-4-isopropoxybenzoyl)-N-methylhydrazinecarboxamide;N′-(4-(benzyloxy)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;3-chloro-N′-(4-(4-fluorobenzyloxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-cyano-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;N′-(4-(1H-benzo[d]imidazol-2-yl)benzyl)-3-chloro-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;3-chloro-N′-(4-(cyclohexylmethoxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;3-cyano-N′-(4-(cyclohexylmethoxy)benzyl)-N′-(2-hydroxyethyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(3-hydroxypropyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-cyano-N′-(3-hydroxypropyl)-4-isopropoxybenzohydrazide;N′-(4-(benzyloxy)benzyl)-3-chloro-N′-(2-cyanoethyl)-4-isopropoxybenzohydrazide;N′-(4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)benzyl)-3-chloro-N′-(2-hydroxybenzyl)-4-isopropoxybenzohydrazide;N′-(4-biphenylylmethyl)-3-chloro-N′-(hydrazinocarbonyl)-4-[(1-methylethyl)oxy]benzohydrazide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)acetamide;[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)carboxamide;N-((1S)-1-{[4-(2-acetyl-1-ethylimidazol-4-yl)-3-fluorophenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-ethylimidazol-4-yl)phenyl]-N-methylbutanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N,N-dimethylbutanamide;N-((1S)-1-{[3-chloro-4-(8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1S)-3-hydroxy-1-{[4-(8-methyl-6-oxo(5H,7H,8H-imidazo[1,2-a]1,4-diazaperhydroin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)ethoxycarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylethoxy)carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(methylamino)carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)(ethylamino)carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)[(methylethyl)amino]carboxamide;N-[(1S)-1-({4-[8-((1S)-1-hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide;(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}-N-methylbutanamide;N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)(3-chloro-4-cyclopropoxyphenyl)carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)acetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)acetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)methoxycarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}-3-methylbutyl)(methylamino)carboxamide;N-{(1R)-1-[4-(4-{(2S)-2-[(3-chloro-4-cyclopropoxyphenyl)carbonylamino]-4-hydroxybutyl}phenyl)-1-methylimidazol-2-yl]ethyl}acetamide;N-((1S)-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-[(1S)-3-hydroxy-1-({4-[8-((hydroxyimino)ethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)propyl][3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamide;N-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl](3-chloro-4-cyclopropoxyphenyl)carboxamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N,N-dimethylbutanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-N-methylbutanamide;(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methylbutanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide;(3S)-3-u{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-{4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}-N-methylbutanamide;(3S)-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide;3-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(3S)-N-methyl-4-{4-[1-methyl-2-(N-methylcarbamoyl)imidazol-4-yl]phenyl}butanamide;(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyldihydrogen phosphate;N-[(1S)-1-({4-[8-(aminoethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[8-(hydroxyethyl)(4-hydroimidazo[1,2-a]pyridin-2-yl)]phenyl}propyl)-2-pyrrolidinylacetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}ethyl)methoxycarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamide;N-[1-({4-[2-((1R)-1-aminopropyl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylamino)carboxamide;N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(2,2,2-trifluoro-isopropoxy)phenyl]carboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxycarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)(methylethoxy)carboxamide;[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-3-hydroxy-1-({4-[2-(1-hydroxy-isopropyl)-1-methylimidazol-4-yl]phenyl}methyl)propyl]carboxamide;[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)carboxamide;((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)methoxy-N-methylcarboxamide;N-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]propyl)-2-azetidinylacetamide;N-{1-[(4-{2-[(1R)-1-(2-oxopyrrolidinyl)ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide;N-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[2-(hydroxyethyl)-1-methylimidazol-4-yl]phenyl}propyl)-2-azetidinylacetamide;((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-ethylimidazol-2-yl}propoxy)-N-methylcarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxycarboxamide;N-[1-({4-[2-((2R)-1-acetylpyrrolidin-2-yl)-1-methylimidazol-4-yl]phenyl}methyl)(1S)-3-hydroxypropyl][4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide;methyl(2R)-2-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}pyrrolidinecarboxylate;N-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]propyl)-2-(dimethylamino)acetamide;N-((1R)-3-carbamoyl-1-{[4-(3-fluoro-8-methyl(4-hydroimidazo[1,2-a]pyridin-2-yl))phenyl]methyl}propyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)acetamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)-N-methylacetamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxy-N-methylcarboxamide;(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl2-(dimethylamino)acetate;N-((1S)-1-{[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)[4-((1S)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide;(3S)-4-[4-(2-acetyl-1-methylimidazol-4-yl)phenyl]-3-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}butyl(2S)-2-amino-3-methylbutanoate;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)acetamide;N-((1R)-1-}4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)methoxycarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}propyl)(methylethoxy)carboxamide;N-{1-[(4-{2-[(1R)-1-(2-oxo(1,3-oxazolidin-3-yl))ethyl]-1-methylimidazol-4-yl}phenyl)methyl](1S)-3-hydroxypropyl}[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)methoxy-N-methylcarboxamide;N-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-(phenylmethoxy)propyl)methoxycarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-(methylethyl)imidazol-2-yl}ethyl)-N-methylacetamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)ethoxy-N-methylcarboxamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamide;N-((1R)-1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamide;N-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamide;N-(1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamide;N-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)methoxycarboxamide;N-(1-{4-[4-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}(2S,1R)-2-hydroxypropyl)acetamide;N-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl][3-chloro-4-(methylethoxy)phenyl]carboxamide;[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]-N-[(1S)-1-({4-[2-((5S,4R)-5-methyl-2-oxo(1,3-oxazolidin-4-yl))-1-methylimidazol-4-yl]phenyl}methyl)-3-hydroxypropyl]carboxamide;N-{(1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-[(4-bromophenyl)methyl]ethyl}[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1S)-2-(1,3-dioxobenzo[c]azolin-2-yl)-1-{[4-(2-bromoacetyl)phenyl]methyl}ethyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1S)-1-{[4-(2-bromoacetyl)phenyl]methyl}-3-hydroxypropyl)[3-chloro-4-(methylethoxy)phenyl]carboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-carbamoylethyl)acetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)acetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-2-hydroxyethyl)methoxycarboxamide;(3R)-3-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}-3-(acetylamino)propanoicacid;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)isoxazol-5-ylcarboxamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-methoxyacetamide;N-((1R)-1-{4-[4-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-4-hydroxybutyl)phenyl]-1-methylimidazol-2-yl}ethyl)-2-furylcarboxamide;N-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamide;N-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-(dimethylamino)acetamide;N-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamide;N-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-azetidinylacetamide;N-(2-{[4-((1R)-2,2,2-trifluoro-isopropoxy)-3-chlorophenyl]carbonylamino}(2S)-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamide;andN-((2S)-2-{[3-chloro-4-(methylethoxy)phenyl]carbonylamino}-3-{4-[1-ethyl-2-(1-hydroxy-isopropyl)imidazol-4-yl]phenyl}propyl)-2-morpholin-4-ylacetamide.39. A composition comprising a pharmaceutical excipient and at least onechemical entity of claim
 1. 40. A composition according to claim 37,wherein said composition further comprises a chemotherapeutic agentother than a compound of Formula I.
 41. A composition according to claim38, wherein said composition further comprises a taxane, a vincaalkaloid, or a topoisomerase I inhibitor.
 42. A method of modulatingCENP-E kinesin activity which comprises contacting said kinesin with aneffective amount of at least one chemical entity of claim
 1. 43. Amethod of inhibiting CENP-E which comprises contacting said kinesin withan effective amount of at least one chemical entity of claim
 1. 44. Amethod for the treatment of a cellular proliferative disease comprisingadministering to a subject in need thereof at least one chemical entityof claim
 1. 45. A method for the treatment of a cellular proliferativedisease comprising administering to a subject in need thereof acomposition according to claim
 37. 46. A method according to claim 42wherein said disease is selected from the group consisting of cancer,hyperplasias, restenosis, cardiac hypertrophy, immune disorders, andinflammation.